Anaesthetic steroids of the pregnane and 19-norpregnane series

ABSTRACT

This invention relates to steroids of the pregnane and 19norpregnane series having anaesthetic properties and compositions containing them. More particularly the present invention relates to such steroids having a variety of substituents in the 2 Beta position, a 3 Alpha -hydroxy group and a 5 Alpha -hydrogen atom and esters and 20-ketals thereof. At the 11-position of such steriods is preferably either two hydrogen atoms or an oxo group. The compounds according to the invention may conveniently be prepared by reaction of an appropriate 2 Alpha ,3 Alpha -epoxypregnane or 19-norpregnane with a reagent which introduces the desired 2 Beta -substituent and various modifications of the compound produced are described to produce compounds within the scope of the invention. The present invention provides compositions containing certain steroids of the pregnane and 19norpregnane series and such compositions generally may be administered intravenously to induce anaesthesia, the invention providing methods of inducing anaesthesia.

ilite tates te Phillipps et al.

[ ANAESTHETIC STEROIDS OF THE PREGNANE ANll) l9-NORPREGNANE SERIES [75]Inventors: Gordon Hanley Phillipps, Wembley;

Christopher Earle Newall, London; Barry Edward Ayres, Amersham, all ofEngland [73] Assignee: Glaxo Laboratories Limited,

Greenford, Middlesex, England [22} Filed: Nov. 11, 1971 [21] Appl. No;197,915

[30] Foreign Application Priority Data Nov. l2, 1970 Great Britain53911/70 [52] US. (1260/2395, 260/239.55 C. 260/397.l S,

[51] Int. Cl. C07c 169/32 [58] Field of Search 260/2395, 397.1, 397.45

[56} References Cited UNITED STATES PATENTS 3,714,352 l/l973 Davis eta]. 424/243 Primary ExaminerElbert L. Roberts Attorney, Agent, orFirm-Bacon & Thomas [57] ABSTRACT This invention relates to steroids ofthe pregnane and l9-norpregnane series having anaesthetic properties andcompositions containing them. More particularly the present inventionrelates to such steroids having a variety of substituents in theZB-position, a 3ahydroxy group and a Sui-hydrogen atom and esters and20-ketals thereof. At the ll-position of such steriods is preferablyeither two hydrogen atoms or an 0x0 group. The compounds according tothe invention may conveniently be prepared by reaction of an appropriate2a,3a-epoxy-pregnane or l9-norpregnane with a reagent which introducesthe desired 2/3- substituent and various modifications of the compoundproduced are described to produce compounds within the scope of theinvention. The present invention provides compositions containingcertain steroids of the pregnane and l9-norpregnane series and suchcompositions generally may be administered intrave nously to induceanaesthesia, the invention providing methods of inducing anaesthesia.

21 Claims, No Drawings ANAESTHETIC STEROIDS OF THE PREGNANE AND I9-NQERENANE Sl Ill This invention is concerned with improvements in or relatingto compounds of the pregnane series having useful anaesthetic activity.

It has long been known that a number of steroids give rise to profounddepression of the central nervous system and act pharmacodynamically asanaesthetics or hypnotics. Such compounds have been the subject ofconsiderable study in an attempt to find anaesthetics to replace suchsubstances as thiopentone sodium normally used but well known to beaccompanied by some degree of hazard and disadvantage. The literatureshows that very many steroid compounds have been studied in this regard.Reviews and discussions of some of the work carried out are to be found,for example, in Methods in Hormone Research" (Edited by Ralph I.Dorfman, Vol. lll, Part A, Academic Press London and New York 1964,pages 4l5-475); H. Witzel, Z. Vitamin Hormon-Fermentforsch 1959, 10,46-74; H. Selye, Endocrinology, 1942, 30, 437-453; S.K. Figdor et al.,J. Pharmacol, Exptl. Therap., 1957, 119, 299309 and Atkinson ct al., J.Med. Chem. 1965, 8, 426-432.

A thorough review ofthe literature indicates that anaesthetic steroidsgenerally possess poor activity and/or long induction periods. With suchcompounds a variety of undesired side effects such as paracsthesia andvein damage have also been noted. Steroids possessing anaestheticactivity hitherto described are generally relative simple pregnanederivatives, oftenhydroxylated in the 3-position, the general trendhaving been in the latter case to study 3,8-hydroxy compounds inpreference to t-hydroxy compounds.

We have now found that certain 3a-hydroxy-2/3- substituted compounds ofthe pregnane series, which are more particularly described hereinafter,have remarkable anaesthetic properties.

The aforesaid 3ot-hydroxy-2B-substituted pregnanes may be generallycharacterised as being steroids of the Sol-pregnane series havinganaesthetic properties and possessing a hydroxy group in theoz-configuration at the 3-position, an oxo group at the 20-position, andeither two hydrogen atoms or an oxo group at the llposition, suchcompounds being further characterised by a substituent R at the2-position in the ,B-configuration as more particularly set outhereinafter.

The expression pregnane series" as used above ineludes not onlycompounds of the conventional pregnane ring structure but also thecorresponding l9-nor compounds. the presence or absence ofa methyl groupat the IO-position having little influence on anaesthetic properties.

The 3a-hydroxy-ZB-substituted pregnanes which we have found to haveespecially valuable anaesthetic activity are the 3a-hydroxy steroids ofthe pregnane and l9-norpregnane series possessing hydrogen atoms in the501- and l7a-positions; two hydrogen atoms or an oxo group in thell-position; an oxo group in the 20- position; and a substitutent R(which is an acyloxy, ether, thioether, alkyl, cycloalkyl, aryl,aralkyl, hydroxy. thiocyanato, nitro-oxy or halo substituent) in theZB-position.

The above 3ot-hydroxy steroids may alternatively carry at theZB-position an azido, sulphonyloxy (e.g. tosyloxy) group, or acylthiogroup.

The substituentR at the .2B-position in the. abovedefined3a-hydroxy-ZB-substituted pregnanes-rnay for example be an acyloxy,ethenthioether, alkyl or cycloalkyl group, for example containing up to9carbon atoms, a monocyclic aryl group (e.g.:aphenyl group) or amonocyclic aralkyl groupleg.abenzylgroup). Acyloxy substituents, whichmay be saturated or unsaturated, include lower (C,-C alkanoyloxy groups,(substituted if desired, for examiplewith-one or more halogen, e.g.chlorine atoms, hydroxy, lower alkoxy, amino and substituted aminogroups), aroyloxy groups, e.g. a benzoyloxy group or aralkanoyloxygroups, e.g. a phenylacetoxy group. Ether substituents, whichmay besaturated or unsaturated, include lower (C C alkoxy groups, loweralkenyloxy groups (e.g. an allyloxy group), cycloalkoxy groups, e.g. acyclohexyloxy group, aryloxy groups, e.g. a phenoxytgroup and aralkoxygroups, e.g. a benzyloxy=group. Thioether groups corresponding to thelast-mentioned oxygen groupsare representative of 2B-thioethersubstituents.

Examples of alkyl groups include especially lower alkyl groupscontaining 1-5 carbon atoms such as methyl, ethyl, propyl, butyl,isobutyl and t-butyl groups. An example of a cycloallkyl group is acyclohexyl group.

Examples of lower alkanoyloxy ZB-substituents include acetoxy,propiouyloxy, butyryloxy, piperidinoaectoxy, morpholinoaceloxy,diethylaminoacetoxy and chloracettitxy groups. Examples of lower alkoxygroups include methoxy, ethoxy, propoxy, isopropoxy. n-butoxy andt-butoxy .groups, the corresponding thio compounds exemplify lower alkylthio substituents.

Lower alkoxy and lower alkylthio substituents at the ZB-position maythemselves be substituted for example by one or more halogen (e.g.chlorine) atoms, lower alkoxy, esterified carboxyl (e.g.ethoxycarbonyl), hydroxy, amino or substituted amino, e.g. morpholinogroups, or a substituted or unsubstituted acyloxy e.g.morpholinoacetoxy, chloroacetoxy or diethylaminoacetoxy group orheterocyclic groups, e.g. a tetrahydrofuranyl group. Alkyl, cycloalkyland aryl groups may also be substituted.

As will be seen the above-defined 3a-hydroxy 2B- substituted pregnaneanaesthetics conform generally to the following skeletal structure:

wherein R is a ZB-substituent as above defined and X represents twohydrogen atoms or an oXo group.

The above-defined 3ct-hydroxy-ZB-substituted-50:- pregnane anaestheticshave been found to induce anaesthesia with generally short inductionperiods, in general the anaesthetic action at suitable doses beingindeed instantaneous; the compounds are thus excellent anaesthetics forinducing anaesthesia which is to be maintained e.g. by an inhalationanaesthetic such as ether, halothane, nitrous oxide, trichloroethyleneetc. The compounds are however capable of maintaining anaesthesia andanalgesia to a sufficient degree to enable various surgical operationsto be conducted without the aid of an inhalation anaesthetic, therequired degree of anaesthesia being maintained if necessary by repeatedadministration (or even continuous administration). Moreover, the saidanaesthetics in accordance with the invention in general give rise to aparticularly low order of undesired side-effects as compared withpreviously described steroidal anaesthetics.

The invention further includes 3ot-esters of the above defined3a-hydroxy-2B-substituted-5a-20-ketopregnane compounds particularlylower alkanoyl esters. for example containing in the alkanoyl group upto carbon atoms. Such esters may also be esters containing one or moresubstituents in the alkanoyl portion e.g. halogen atoms (e.g. fluorineand chlorine atoms), carboxy groups or amino or substituted amino, e.g.diethylamino groups etc. The invention additionally extends to -ketals,for example ethylene ketals, of the above 3a-hydroxy anaesthetics andtheir esters. Generally the induction period with a 3-ester or aZO-ketal is longer than that with a corresponding t-hydroxy 20-keto-pregnane compounds. Both the 3a-hydroxy compounds and thecorresponding 3-esters and 20-ketals may be regarded as central nervoussystem depressants and thus in suitable doses may also be used ashypnotics or sedatives.

The above-defined 3a-hydroxy-2B-substituted-5apregnane anaestheticsteroids and the corresponding 3a-esters and ZO-ketals are hereinaftercollectively referred to as 3a-oxygenated-2B-substituted-Sapregnaneanaesthetics.

The above-defined 3oz-oxygenated-2B-substituted- Set-pregnaneanaesthetics may contain further substitution for example at the If) and2l-positions. Thus the lo-position may be substituted by one or twolower alkyl groups e.g. methyl groups, a lower alkoxy group e.g. amethoxy group, or by a halogen atom e.g. fluorine or chlorine. Theconfiguration of the 16- substituent may be 01- or (3-. The 2l-positionmay for example be substituted by alkanoyloxy (C groups e.g. an acetoxygroup, or by halogen e.g. bromine.

The various substituents in the steroids according to the invention ofthe pregnane and l9-norpregnane series may if desired be themselvessubstituted by substituents which confer water solubility, e.g. aminoand substituted amino groups in salt form, or carboxylate groups.

The 3a-oxygenated-ZB-substituted-5a-pregnane anaesthetics may beformulated as convenient, following generally known pharmaceuticalpractices, with the aid of one or more pharmaceutical carriers orexcipients. By the term pharmaceutical as used herein we includeapplications to both human and veterinary medicine. For anaestheticpurposes the steroids will normally be given by injection and thus oneaspect of this invention comprises an anaesthetic composition forparenteral administration comprising a 30t-oxygenated-2B- substitutedpregnane compoundas above-defined in a parenterally acceptable vehicle.

The xysenate -%-"b tut9rfi r aesthetics are generally new compounds withF566;-

4 ception of 2B-thiocyanato-3a-hydroxy-Sa-prcgnan- 20-one. the newcompounds comprising a further aspect of the invention. Generally the ll-oxo compounds possess better anaesthetic properties in terms ofinduction time and/or degree of action than the corresponding 1l-unsubstituted compound.

Particularly preferred new compounds according to the invention byvirtue of their excellent anaesthetic properties and short inductionperiod are the following:

2,8-methoxy-30t-hydroxy-5a-pregnane-l l,20-dione,-

ZB-ethoxy-3a-hydroxy-5a-pregnane-l l,20-dione,

2,8-isopropoxy-3a-hydroxy-5a-pregnane-l 1,20-

dione,

ZB-n-propoxy-3a-hydroxy-5a-pregnane-l 1,20

dione, 2,B-(2-chloroethoxy)-3a-hydroxy-5a-pregnane- 11,20-dione,2/3-methyl-3a-hydroxy-5oz-pregnane-l l.20-dione.2B-bromo-3a-hydroxy-Sa-pregnane-l l,20-dione,2,8-chloro-3a-hydroxy-Sot-pregnane-l 1,20-dione.2B-iodo-3a-hydroxy-5a-propane-l l,20-dione,

2,B-thiocyanato-3a-hydroxy-Sa-pregnane-l 1,20-

' dione,

2,8-acetoxy-3a-hydroxy-5a-pregnane-l 1,20-dione,

2,8-ethoxy-3a-hydroxyl 9-nor-5a-pregnane-l 1,20-

dione,

2B-chlo ropropoxy-3a-hydroxy-5ot-pregnane-l 1,20-

dione,

3a-hydroxy-2B-piperidinoacetoxy-Sa-pregnanel 1,20-dione citrate,3a-hydroxy-Zfi-propionyloxy-Sa-pregnane-l 1,20-

dione, 2Bn-butoxy-3oz-hydroxy-5a-pregnane-l 1,20-dione,

and 2,8-n-butyl-3a-hydroxy-5a-pregnane-l l,20-dione. Many of the3a-oxygenated-ZB-substituted-Sapregnane anaesthetics are poorly solublein water. We have found however that they may be formulated forparenteral administration in an aqueous solution of a parenterallyacceptable non-ionic surface active agent. The non-ionic surface activeagents used for the purpose of this invention are generally those of thewater soluble type, conveniently having an HLB value of at least 9,preferably at least about 12, advantageously at least about l3.Preferably the HLB value ofthe surface active agent is not greater thanabout 15 although it may, for example, be as high as 18. The surfaceactive agent must naturally be one which is physiologically compatible,ie of itself give rise to no physiologically unacceptable side effectsin the dosages employed in the intended species to be treated (man oranimal). Surface active agents for use in accordance with the inventionare for example to be found amoung the following non-ionic surfactantsand classes of surfactants: Polyoxyethylated derivatives of fatty(Cl2-C20) glyceride oils, e.g. castor oil. containing from 35 to 45oxyethylene groups, per mole of fatty oil. Polyoxyethylene ethers(containing from 10 to 30 oxyethylene groups) of long chain alcohols(containing for example from 12-18 carbon atoms).

Polyoxyethylene-polyoxypropylene ethers containing from 15 to 35 andfrom 15 to 30 oxyethylene and oxypropylene groups respectively.Polyoxyethylene ethers (containing from 6 to 12 oxyethylene groups) ofalkyl phenols the alkyl groups of which preferably contain 6l0 carbonatoms.

Polyoxyethylated (containing from to 30 oxyethylene groups) fatty acid(e.g. Cl2-l8) esters of sugar alcohol anhydrides e.g. sorbitan ormannitan. Long chain (e.g. C10-l6) alkanoyl monoand dialkanolamides (thealkanol portions of which for example contain l-5 carbon atoms) forexample lauroyl monoand di-ethanolamides. Polyethylene glycolesters(containing from 6-40 ethylene oxide units) of long chain fatty acidscontaining, for example, 12-l8 carbon atoms, e.g. polyethylene glycolmonooleate (containing for example 8 ethylene oxide units).

Examples of non-ionic surface active agents, of the foregoing types,useful in accordance with the invention include:

Cremophor EL, a polyoxyethylated castor oil containing about 40 ethyleneoxide units per triglyceride unit;

Tween 80, polyoxyethylene sorbitan monooleate containing about ethyleneoxide units;

Tween 60, polyoxyethylen e sorbitan monostearate containing about 20ethylene oxide units; and

Tween 40, polyoxyethylene sorbitan monopalmitate containing about 20ethyleneoxide units.

The expression solutions is used herein to denote liquids which have theappearance oftrue solutions and are thus optically clear and capable ofpassage, for ex ample, through a micro-porous filter, irrespective ofwhether such solutions are true solutions in the classical chemicalsense and irrespective of whether they are stable or metastable. Thus itmay be that the steroid is associated with micelles. The solutions ofthis invention, irrespective of their precise physical nature, behave astrue solutions for the practical purpose of intravenous injection.

The proportion of surface active agent to be used in the compositions ofthis invention depends upon its nature and upon the concentration ofsteroid desired in the final composition.

ln preferred composition according to the invention the proportion ofsurfactant is preferably at least 5% by weight and advantageously above10% by weight. A very convenient proportion of surfactant has been foundto be 20% byweight but and up to 50% may be used. The proportionsofsurfactant are expressed by weight in relation to the total volume ofthe composition.

As will be clear, the proportion of steroid in the aqueous solutionaccording to the invention depends upon the nature and amount of surfaceactive agent used. The composition will generally contain at least 1mg/ml of steroid and solutions can be made containing for example up to67 mg/ml of steroid or even 10 mg/ml.

In a preferred method of preparing the solutions according to theinvention the steroid is first dissolved in the selected surfactant forexample, with heating and the resulting solution dissolved in water.Alternatively the steroid may be dissolved in a volatile organic solventadvantageously having a boiling point of less than about 80C which ismiscible with the surface active agent such as a volatile loweraliphatic ketone e.g. acetone or methyl ethyl ketone or a volatilehalogenated hydrocarbon e.g. chloroform or methylene chloride. Acetoneis particularly preferred for this purpose. The surface active agent isthen added to this solution. the organic solvent removed by evaporation,for example by passing a stream of an inert gas through the solutione.g. nitrogen and the resulting solutionof steroid in surfactant ismixed with water.

The solutions may also be prepared by shaking the steroid with anaqueous solution of the surface active agent.

in all cases simple tests enable one to determine the relativeproportions of surface active agent required.

Naturally those 3a-oxygenated-2B-substituted-Sapregnane anaestheticswhich are water soluble may be formulated for injection in a sterileaqueous medium in the absence of a surface active agent.

The anaesthetic solutions according to the invention are generallyadministered by intravenous injection although as is known in theanaesthetic art in certain cases, e.g. with young children,intramuscular injection might be preferred.

As is usual in the case of anaesthetics, the quantity of steroid used toinduce anaesthesia depends upon the weight of the individual to beanaesthetised. For intravenous administration in the average man a doseof from 0.25 to 3.5 mg/Kg will in general be-found to be satisfactory toinduce anaesthesia, the preferred dose being within the range of from0.4 to 2.0 mg/Kg. Generally a dose of about 1.0 mg/Kg is verysatisfactory. The dose will naturally vary to some extent dependent uponthe physical condition of the patient, and the degree and period ofanaesthesia required, all as is well known in the art. It is thuspossible by adjustment ofthe dose to achieve durations of anaesthesiavarying from about 10 minutes to up to an hour or more. lfit is desiredto maintain prolonged anaesthesia, repeated doses of the solutions ofthis invention may be used, such repeated doses being generally eitherof the same order or lower than the original dose. Alternativelycontinuous administration may be undertaken at for example a rate of0.09l.8 mg/Kg/Min.

Where the anaesthetic solutions are administered intramuscularly, higherdoses are generally necessary.

According to a further feature of the present invention there isprovided a process for the preparation of 3a-hydroxy steroids of the'pregnane and 19- norpregnane series possessing hydrogen atoms in theand Hot-positions; two hydrogen atoms or an oxo group in the ll-position; an oxo group in the 20- position; and a substituent R (whichis an acyloxy, ether, thioether, alkyl, cycloalkyl, aryl, aralkyl,hydroxy, thiocyanato, nitro-oxy or halo substituent) in the 2B-positionand Bot-esters thereof (with the exception of2B-thiocyanato-3a-hydroxy-Sa-pregnane- 20-one) which comprises reactinga 2a,3a-epoxide of the pregnane or l9-norpregnane series possessinghydrogen atoms in the 5ozand Hot-positions; two hydrogen atoms or an oxogroup in the ll-position; an oxo group in the 20-position and, ifdesired, a 16,17-double bond with a compound of formula RH or with areaction system producing R and a cation followed, where the initialproduct carries a 311 -hydroxy group is deprotonated form, by treatmentwith a source of protons to form the desired free 3a-hydroxy group, andwhere an ester of the 3oz-hydroxy steroid initially produced is desired,by subsequent acylation thereof; wherein a A -steroid is produced, thisproduct being subjected to hydrogenation of the 16,17-double bond.

The preparation of compounds having a ZB-halo substituted isconveniently effected by reaction of the 2a,3a-epoxide with an aqueoussolution, preferably concentrated. ofa halogen hydracid. This reactionmay also be carried out in a two-phase system, the steroid epoxide beingdissolved in a water-immiscible organic solvent e.g. methylene chlorideor chloroform. in another modification of this reaction the steroidstarting material may be reacted with the hydracid in an organic solventunder substantially anhydrous conditions. Suitable solvents for thislast-mentioned reaction include methylene chloride, chloroform, etherand dioxan.

For the preparation of ZB-fluoro compounds, it may be convenient toreact the epoxy compound under anhydrous conditions in solution withhydrogen fluoride or a complex thereof with a carbamic or thio carbamicacid'or esters or amides thereof, e.g. urea. Solvents which areconvenient for this reaction include tetrahydrofuran, dimethylformamide,halogenated hydrocarbons e.g. chloroform, or the hydrogen fluoridecomplex itself e.g. the hydrogen fluoride-urea complex.

The-general use of hydrogen fluoride complexes as above referred to forthe production of steroid fluorhydrins is described in Canadian PatentNo. 690,333.

The reaction of the steroid epoxide with a halogen hydracid may beeffected at various temperatures e.g. at from l to 100C, for example, atambient temperature e.g. C.

The ZB-halo compounds, particularly the ZB-chloro and ZB-bromo compoundsmay also be prepared by reacting an appropriate epoxide with anappropriate halo-ethanol. The reaction is conveniently effected in thepresence of an acid catalyst, for example sulphuric acid. SomeZB-chloroethoxy steroid will be formed simultaneously when chloroethanolis used, as is indicated hereinafter.

The above-defined 2B-substituted 3a-hydroxy-5apregnanes having an ethersubstituent in the 23- position may be prepared, for example by reactinga corresponding 2a,3a-epoxy-5a-pregnane with an anhydrous alcohol, thealcohol being chosen to provide the desired ZB-substituent.

Where a chloroalkoxy derivative is required the 20:,3a-epoxide may bereacted with a chloroalkanol although as indicated above some 2B-chloroderivative is usually formed simultaneously when chloroethanol is used.ZB-Chloroalkoxy derivatives of this type can be used to preparecorresponding 2B-aminoalkoxy derivatives by reaction with ammonia orprimary or secondary amines, which may be cyclic or acyclic, e.g.,morpholine. The replacement of chlorine takes place only withdifficulty, for example by heating at 100C. for 24 hours, and it isadvantageous first to protect the 20- keto group by ketal formation. Theketal group can readily be removed subsequently by conventional meanssuch as acid hydrolysis.

In general, the reaction with an alcohol is preferably effected in thepresence of an acid or basic catalyst. Suitable catalysts include thoseknown for use in the production of ethers by the opening of epoxiderings with alcohols. The reaction is preferably catalysed using an acidcatalyst, forexample, sulphuric, perchloric and oxalic acid, aluminumchloride and boron trifluoride. Basic catalysts which may be usedinclude alkalimetal alco'holates derived from the alcohol used in thereaction; Under such basic conditions the Zia-hydroxy group in theinitial product may be partly in deprotonated form and may requireregeneration by addition of a source of protons. The reaction willnormally be carried 'out in an excess of the reactant alcohol as solventbut if desired, an aprotic solvent may be ,present, e.g. an ethersolvent such as diethylether ortetrahydrofuran, a hydrocarbon e.g.benzene or a halogenated hydrocarbon e.g. chloroform or methylene chloride. The reaction is preferably effected at about ambient temperaturealthough elevated temperatures, for example at about 50C. may, ifdesired, be used.

In order to form ZB-(esterified carboxy-alkoxy)-3ahydroxy steroids, a2a,3a-epoxide may be reacted with a cyanoalkanol to form aZB-cyanoalkoxy derivative which may then be treated with an alcoholunder acid conditions to form an iminoether salt which on hydrolysisyields the desired ester.

The preparation of ZB-acyloxy substituted 5apregnane anaesthetics ispreferably effected by reacting the corresponding2a.3a-epoxy-5a-pregnane with a carboxylic acid. In general, the acidreactant acts as a catalyst for the acylation reaction and whereliquid-at the reaction temperature, an excess thereof may be used as asolvent for the reaction. However, other solvents may be used, forexample the solvents referred to above in relation to ZB-ethers. Thereaction is preferably effected at elevated temperatures.

It is particularly useful to react the 2a,3a-epoxide with achloroalkanoic acid, particularly chloroacetic acid, to yield thecorresponding ZB-chloroalkanoyloxy derivative. In the case ofchloroacetic acid, it was found preferable where a Zia-hydroxy steroidwas required to carry out the reaction benzene at moderate temperaturese.g. 50C since higher temperatures e.g. refluxing, gave a significantproportion of 2B,3a-dichloroacetoxy ester. The ZB-chloroalkanoyloxycompounds can be subjected to halogen exchange, e.g. to form 26-iodoalkanoyloxy derivatives which can then be reacted with primary orsecondary amines to give 23- aminoalkanoyloxy derivatives.

Certain Zfl-(a-haloacyloxybutoxy) compounds according to the invention,particularly 2B-6-(ahaloacyloxy)butoxy compounds, may be prepared byreaction of the corresponding 201,3a-epoxide with an appropriatea-halo-carboxylic acid in the presence of tetrahydrofuran, the latterentering into the reaction. In general the 5-(a-haloacyloxy)-butoxyproduct will predominate but some ZB-(a-haloacyloxy)steroid will also beformed.

Thus, for example, in one experiment when a 201,301- epoxide reactedwith chloroacetic acid in tetrahydrofuran, the products included 20% ofZB-chloroacetoxy steroid and 60% of 2,8-(8-chloroacet0xy)-butoxysteroid. The reaction may generally be effected under conditionssuitable for the preparation of ZB-acyloxy compounds as hereinbefore setforth. 28-55(01- Haloacyloxy)butoxy steroids can be subjected tohydrolysis to yield the corresponding ZB-S-hydroxy-nbutoxy-steroids.2/3-(8-Chloroacyloxy)butoxy steroids may be subjected to halogenexchange to form, for example, the corresponding iodoacyloxy-butoxysteroid which may then be reacted with ammonia or a primary or secondaryamine to yield a corresponding aminoacyloxy-butoxy steroid.

Steriods having a thioether group in the 2B-position niently in the formof its etherate. The reaction is conveniently effected in an ethersolvent.

ZB-Acylthio steroids can be formed by reaction of a thiocarboxylic acidwith the 2a,3a-epoxide. An acid catalyst is preferably present, forexample a Lewis acid such as BF conveniently in the form of an etherate.The reaction is conveniently effected in an ether solvent.

2B-Nitro-oxy-3a-hydroxy-5a-pregnanes may be prepared by the reaction ofthe corresponding 2a,3aepoxides with concentrated nitric acid in anorganic solvent. Suitable solvents include etheric solvents e.g. diethylether, dioxan, tetrahydrofuran, diglyme, ethyleneglycol monomethylether. The reaction may for example be effected at ambient temperature.

2,B-Thiocyanato-3a-hydroxy-5a-pregnanes may be prepared by reaction ofthe corresponding 201,30:- epoxides with thiocyanic acid or an alkalimetal (e.g. sodium or potassium) thiocyanate or ammonium thiocyanate,conveniently in an etheric solvent for example of the type referred toin the last-preceding paragraph, in the presence of an acid catalyste.g. perchloric acid when using thiocyanates. The reaction may, forexample, be effected at ambient temperature.

ZB-Alkyl, cycloalkyl, aryl or aralkyl-3a-hydroxy-5apregnanes may bereadily prepared from the corresponding 2oz,3a-epoxides by reaction witha lithium di- (alkyl, cycloalkyl, aryl or aralkyl) cuprate convenientlyin an etheric solvent e.g. diethyl ether or a hydrocarbon solvent e.g.hexane. The reaction may be effected in known manner for example asdescribed by Herr et al. (J.A.C.S. 1970, 92, 3813). The ZB-substitutedsteroid initially formed has at the 3a-position an O-metal substituentwhich is subsequently converted to OH by treatment with a source ofprotons such as aqueous ammonium chloride.

3a-Acyloxy esters of the 3a-hydroxy-ZB-substitutedpregnane anaestheticsmay be prepared from the corresponding 3a-hydroxy compounds by acylationin known manner. This acylation may for example be effected using areactive derivative of the carboxylic acid such as an anhydride or acidhalide. In general, the acylation is preferably effected in an aproticsolvent, for example, a halogenated hydrocarbon e.g. chloroform ormethylene chloride. The acylation is preferably effected in the presenceof an acid binding agent such as a tertiary organic base, for example,pyridine.

23,3a-Dihydroxy-5a-pregnanes may be prepared, for example, by hydrolysisof the corresponding 2a,3aepoxy-Sa-pregnane. This hydrolysis isgenerally effected in an aqueous medium, preferably containing a watermiscible aprotic organic solvent such as acetone or tetrahydrofurangenerally to aid the solubility of the steroid. The hydrolysis isadvantageously effected under acidic conditions, for example, using anaqueous solution of an inorganic acid e.g. perchloric or sul phuricacid.

Compounds according to the invention wherein R represents an azido groupmay be prepared, for exam ple, by reacting a corresponding 2a,3a-epoxysteroid with an alkali metal azide e.g. sodium azide, in the presence ofa source of protons. The reaction may conveniently be effected in asolvent, for example dimethyl sulphoxide or dimethyl formamide. Suitableproton sources comprise mineral acids such as sulphuric acid and boricacid. The reaction is preferably effected at an elevated temperature.

2B-Azido compounds according to the invention may also be prepared byreacting a corresponding 2B- sulphoxide. The reaction is preferablyeffected at an elevated temperature. Such a tosyloxy derivative can beprepared by reaction of the 2a,3a-epoxide with substantially anhydrousp-toluene sulphonic acid.

As above-mentioned, the introduction. of the desired substituent bysuitable reaction with a 2a,3oz-epoxide may be effected upon a Acompound, the double bond thereafter being reduced to produce thedesired saturated ring structure, the introduction ofthe desired2,8-substituent being effected by the methods described above for thecorresponding saturated compounds. Reduction of the A -double bond isconveniently effected by hydrogenation preferably in an organic solvent,for example methanol, ethanol, propanol, diethylether, tetrahydrofuran,chloroform, methylene chloride or ethyl acetate. As hydrogenationcatalyst, palladium catalysts for example palladised charcoal, Raneynickel and platinum catalysts may be used. The hydrogenation is furtherpreferably effected in the presence of a tertiary base e.g.triethylamine.

ln hydrogenating the above-described Set-pregnl6-enes, conditions shouldbe chosen to avoid reducing substituents already present in themolecule.

Compounds according to the invention having a 16-, position alkyl groupmay be prepared by known-methods. l6a-Alkyl compounds may also beprepared by reacting a corresponding A -steroid with an appropriatelithium dialkyl, cuprate, preferably in the presence of an ethericsolvent, e.g. diethyl ether. This reaction may, if desired, be effectedsimultaneously with the introduction of a ZB-alkyl group as hereinbeforedescribed, that is by reacting a 2a,3a-epoxy-20-keto-5a pregn-l6-enewith the lithium dialkyl cuprate reagent.

The 5a-pregn-l6-enes are also useful intermediates for the preparationof compounds having a substituent at position 16, for example, chloro,and alkoxy substituents. Such substituents may be introduced in knownmanner.

2l-Acyloxy substituents may be introduced into the above-defined2B-substituted-30z-hydroxy-5a-pregnane compounds or into intermediatesused in their production by known methods. Such methods includeacyloxylation, and especially acetoxylation of the corresponding2l-unsubstituted compound with a lead tetraacylate preferably in thepresence of a Lewis acid. The 3a-hydroxy group of the starting compoundsmay if necessary be protected in known manner.

2l-Acyloxy compounds may also be prepared in known manner via thecorresponding 2l-chloro, 2lbromo or 2l-iodo compounds as described inour Belgian Patent No. 752,165.

Compounds according to the invention having a 301- amino or substitutedamino-alkanoyloxy group may be prepared for example from thecorresponding 30:- haloalkanoyloxy compounds by reaction with ammonia oran appropriate amine. The reaction may conveniently be effected in asolvent for example a halogenated hydrocarbon e.g. methylene chloride.

, Compounds according to the invention having a basic centre, forexample ZB-aminoalkoxy or alkanoyloxy or Swaminoalkanoyloxy compoundsmay, if desired, be converted into acid addition salts thereof.

Known methods may be used to prepare such salts" which may be withinorganic acids (e.g. hydrochloric acid, sulphuric acid or phosphoricacid) or organic EXAMPLE 1 2B-Fluoro-3a-Hydroxy-5 a-Pregnanel 1,20-Dine.

Anhydrous hydrofluoric acid (50 ml.) was added slowly to urea (40 g.) togive a colourless liquid. To 1 1 ml. of the liquid was added211,3a-epoxy-S a-pregnanell,20-dione (650 mg.), and the clear solutionwas stirred at room'temperature overnight. It was poured into saturatedsodium bicarbonate solution (250 ml), and the white precipitate waswashed with water, dried over sodium sulphate and evaporated to give awhite foam (565 mg). Recrystallisation from acetone-petrol gave thetitle compound m.p. l74l78, [01],, +1 14.

EXAMPLES 2-29 Various compounds according to the invention were preparedaccording to methods A-D below the amounts of various reactants anddetails of the products being set out in the following Tables.

Method A Preparation of 2B-halo-3a-hydroxy-5a-pregnanes'The-2a,3a-epoxy-5a-pregnane was dissolved in chloroform and thesolution was treated with the appropriate'hydrohalic acid. The mixturewas stirred vigorously for approximately one-half hour at roomtemperature and then poured into chloroform. The organic solutionGeneral Et OAc a Ethyl Acetate Formula trip triturated 2 was washed withwater, then dilute sodium bicarbonate solution, then again with water.dried over sodium sulphate, and evaporated to give a crystalline residuewhich was purified by recrystallisation.

Method B appropriate alcohol. and concentrated sulphuric acid (catalyst)was added. The solution was stirred for approximately one-half hour-.,and then poured into water to give a white crystalline precipitate whichwas filtered off and dried in vacuo over phosphorus pentoxide to givethe product.

Method C Preparation of 2,8-alkoxy-3a-hydroxy-Sa-pregnanes.

The 2a,3a-epoxy-5a-pregnane in ether was treated with the appropriatealcohol. Boron trifluoride etherate was added to the solution and themixture was stirred at room temperature for 1 hour. The solution wasneutralised with sodium bicarbonate solution. The organic layer waswashed with water and dried over anhydrous sodium sulphate. Evaporationof the solvent gave the crude product which was purified by preparativethin The 2B-substituted-3a-hydroxy-Sa-pregnl 6-ene in ethyl acetate andtriethylamine was hydrogenated over 5% palladium-on-charcoal catalyst atatmospheric pressure for 30 minutes. The catalyst was filtered off andthe filtrate was evaporated to a white solid. Recrystallisation gave thecrystalline product.

d decomposition Ex; zx Method of Weight of Amount of Amount: ofCrystal'l- Yeild M. pt. [a] Amount of No. Brepamlion epoxide(mg) reagentsolvent isatzion (mg) ('C) -Catalyst HY(ml) (ml) solvent 7. =0 C1 A 68215 25 ECOAC 413 185-189 +117 3 =0 Br A 502 10 30 acetone/ 483 206-210+106 I ether 4 a =0 1 A 600 5 25 EtOAc/ 395 108-109 +109 petrol 5 H -HC1 A 303 6 1O EtOAc 137 175-179 6 H -H Br A 356 7 2O EtOAc/ 144 171-175+117 ether 7 H =0 CH 0- B 200 20 175 163-164 +109 0. l

8 H =13 C H O- B 500 30 340 74-78 +100 0. 15 9 H =0 l. C l-! O B 500 25acetone/ 300 154-158 -l-103.5 O 5 petrol 10 H HO GlC H O- B 500 25 360+87 5 O. 5 l 1 i H "H GH O- I 500 385 176-179 +102 0 l Cont/d.

13 1Co111inued... 14

Z X Y Mefi'od of Weight of Amount of Amount ofCrystall- Yield M.pt [011DAmount of Ex. Pzeparaiion epoxide(mg) reagent solvent isation (mg) (6)Catalyst No. HY(ml) (ml) solvent (ml 12 11 -H2 c n o- B 1.4g 90 ether/1.44 114-121 +sa- 0.42

petrol 13 11 =0 EC3H7O- 13 2.0g e0 acetone/ 1.24;; 108-110 +96 0.5

petrol Z 1 H =0 ca oc 1 o B3 2.0g 50 lAlg +955 0.5 15 H =0 Om B 519 1S8+98 0.5 16 n =0 c 11 o- 15 1.0g ether/ 196-202 0.25

petrol trit 17 11 =0 m o B 1.0g 30 aq.acetone 130 165-1 71 +s3.5 0.3

2 1s 11 =0 CH CHCPEO-B 660 4 e 316 +595 3 drops 1 .1113 =0 c1 A 200 7 sEtOAc/ 13o 21e-22a +99- v petrol 2o aMe =0 MeO- B 200 10 EtOAc/ 160206-210. +97.5 0.05

' petrol 21 H =0 2-C1(GI c 330 5 25 31o +87.5 5 drops 22 H =0 p G H C c500 2 480 +99" 10 drops 71 1 =0 fl pc 1.0,; 63. azetmebdml 325 229-231+79.2 1.0 ml.

r 2n 1: =0 mm B 500 5 acetone 2.23 197-202 +91.3 0.2

A H ,I 0-c 1.0g 5 so r +s2.7 10 drops 1. Product was purified bypreparative thin layer chromatography on silica gel in chloroform beforerecrystallisation.

2. The organic solution was washed with sodium bisulphite instead ofsodium bicarbonate.

3. The reaction mixture was diluted with potassium bicarbonate (10%)before dilution with water.

4. The product was extracted with ether and the extract washed withwater and dried over sodium sulphate. Evaporation of the ether gave aproduct which was purified by preparative TLC on silica in ethylacetate/petrol.

5. The product was extracted with ether.

6 After 1 hour, the reaction was incomplete and a further portion of BFetherate was added.

7. The solution was neutralised with potassium hydroxide instead ofsodium bicarbonate.

' 8. The solution was heated gently to keep the steroid in solution.

9. The acids used in the reaction were of the following strength: HClconcentrated, H1 55%, and HBr 48%.

Compounds prepared by Method D Y a6 l-l ix. 1 X Weight of Amount of NEt(ml.) Catalyst (..ryst:a].l-- Yield M. pl: [0:] No. starting EtOAc(ml)(mg) isation (mg) (0) D material(mg) solvent 26 Cl =i-l 50 0.1 EtOAo/ 35178-133 +105 petrol 27 ca.0- =H 50 10 0.1 10 EtOAe/ 42 178-180 +102 Ipetrol (1. =0 65 20 0.15 EtOAc 55 189-193 +117 2" CEi.,O 0 150 35 0.2EtOAc/ 135 161-163 +108 J petrol EXAMPLE 25 Sodium (70 mg.) wasdissolved in dry metlianolfi Ba-Hydroxy-ZB-Methoxy-S a-Pregnane-l1,20-Di0ne a. In a series of reactions, 2a,3a-epoxy-5a-pregnanell,20-dione (100 mg. 0.3 m.mole) was reacted at ambient temperature withmethanol (5 ml) in the presence of a variety of catalysts. The catalystused, the amount thereof and the reaction time are given for each casein the following table. With the exception of the reaction catalysed byAlCl the reaction mixture was neutralised with potassium bicarbonatesolution after the time given in the table. Water was then added to theneutralised reaction mixture and the precipitated title compound wasfiltered off and dried in vacuo over phosphorus pentoxide.

The AlCl catalysed reaction mixture was dilutedwith dilute aqueoushydrochloric acid and the resulting solution was extracted withchloroform, the extract was evaporated and the crude product wasrecrystallised to give the title compound.

Reaction of 2a.3a-epoxy-5a-pregnane-l 1,20- dione with methanol in thepresence of various catalysts action Catalsyt Amount Molar ReactionIsolated No. Eq. Time Yield 7:

1 H 50 0.0lml 0.6 10 min 57 (conc.) 2 H 50 0.1 ml 6 5 min 64 (conc.) 3 HSOAZN) 0.1 ml 0.3 1 hr 56 4 HClO 0.0lml 0.3 20 min 61 (7071) 5HCl(conc.) 0.0lml 0.4 20 min 68 6 z 15mg 0.3 25 min 60 7 (CO HM mg 1 72hr 76 ZH O 8 TsOH.H,O 55mg 1 10 min 70 9 BF .Et O 0.0lml 0.6 min 7l.5 l0AlCl 40mg l 40 min 70 l l SOC! 0.025ml 1 10 min 69 I2 POCI 0.0lml 0.4 10min 63 13 Me SO 0.0l5ml I 0.5 2.5 hr 69 14 crucoci 0.0lml 0.5 10 min 73b. The reaction of 20z,30z-epoxy-5oz-pregnane-l1 ,2 0 dione with sodiummethoxide ml), and to the resulting solution of sodium methoxide (about166 mg,) was added 2a,3a-epoxy-5a-pregnane- 1 1,20-dione mg). Thesolution was refluxed for 5 days, then water was added, and the mixturewas neutralised with dilute hydrochloric acid and extracted intochloroform. The extract was dried over sodium sulphate and evaporated toa brown oil which was purified by preparative tlc in ethylacetate/petrol l/l The title compound was recrystallised from ethylacetate/petrol (21 mg).

EXAMPLE 31 3a-Hydroxy-ZB-methyI-Sa-pregnane-l 1,20-dione A 1.6 molarsolution of methyl lithium in ether (30 ml.) was added to stirredsuspension of cuprous iodide (4.56 g.) in dry ether (100 ml.) undernitrogen at '20. A cold solution of 2a,3a-epoxy-5a-pregnane-l1,20- dione(1.33 g.) in dry ether (20 ml.) was then added and the mixture wasmaintained at 0 for 40 hours and then at room temperature for 4 hours.The mixture was then poured into aqueous chloride solution and extractedinto ethyl acetate. The organic extract was washed with water. dried(MgSO and evaporated in vacuo. The residue (2.9 g.) was purified bypreparative tie and crystallisation from methyl acetate/petroleum etherto give the title compound (0.5 g.) m.p. 142146 [01],, 121+(c 0.8).

EXAMPLE 32 21-Bromo-3a-hydroxy-ZB-methoxy-Sa-pregnanel 1,20-dione Asolution of 3a-hydroxy'2B-methoxy-5a-pregnane- 11,20-dione (2g.) inmethanol (15 ml.) was treated with hydrobromic acid in glacial aceticacid (3drops). The mixture was stirred at room temperature and bromine(530 mg.) in methanol (1.45ml.) was added'dropwise over a period of 30minutes. The mixture was stirred for a further 30 minutes and pouredinto water, stirred, filtered, washed with water and dried. Purificationby preparative tlc, followed by crystallisation from ethyl acetate andpetrol gave the title compound (250mg) as colourless plates; m.p.l85-l88 [a];, 104.

EXAMPLE 33 2 l -Acetoxy-Ba-hydroxy-ZB-methoxy-Sa-pregnanel l,20-dione.

rification by preparative tlc followed by crystallisation from ethylacetate and petrol gave the title compound (230 mg.) as colourlessplates; m.p. l77-l80 [01] 112.

EXAMPLE 34 23,3 a-Dihydroxy-Sa-pregnane-l l,20-dione2a,3a-Epoxy-5a-pregnane-ll,20-dione (207 mg.) in hot tetrahydrofuran (6ml.) was treated with perchloric acid (60%, 0.05 ml.) in tetrahydrofuran(2 ml.) and water (2 ml.). The reaction mixture was concentrated to ml.,allowed to stand for minutes and boiled for 30 minutes with theconcurrent addition of water. The mixture was poured into ethyl acetate,and the aqueous layer was extracted with ethyl acetate. The combinedorganic extract was washed with water, dried over sodium sulphate andevaporated to a crystalline mass which was purified by preparative TLCto give the title compound (70 mg.) as colourless crystals, m.p.l94-l98, [11],, l03.5.

EXAM PLE 35 3a-l-lydroxy-2,8-thiocyanato-5a-pregnane-l l,20-dione 2943a-Epoxy-5a-pregnaned1,ZO-dione (500 mg.)

EXAMPLE 36 2B,3a-Dihydroxy-5a-pregnane-l l,20-dione Znitrate2a,3a-Epoxy-5a-pregnane-11,20-dione (1.0 g.) was dissolved in ether (50ml.) and to the stirred solution was cautiously added fuming nitric acid(0.5 ml.). The solution was stirred at room temperature overnight andthen poured into ether (100 ml.) and water (100 ml.). The ether layerwas washed with water, dilute potassium bicarbonate solution, and water,dried over sodium sulphate and evaporated to a yellow oil (1.24 g.). Theproduct was purified by preparative tlc to give the title compound as awhite solid, m.p. l70-l76, [a],, 74.

EXAMPLE 37 3a-Acetoxy-2B-ethoxy-Sa-pregnane-l l,20-dione2B-Ethoxy-3a-hydroxy-5 a-pregnane-l l,20-dione (500 mg.) in drymethylene chloride (5 ml.) at 0-was treated with pyridine (2.0 ml.) andacetic anhydride (2.0 ml.). After 24 hours, methylene chloride wasadded, and the solution was washed with dilute hydrochloric acid andwith water. lt was then dried over sodium sulphate and evaporated to anoil. The title compound (350 mg.) was obtained .as a colourless foam,[01],, 132.

EXAMPLE 38 ZB-Ethoxy-3oz-propionyloxy-Sa-pregnane-l l,20-dione2B-Ethoxy-3a-hydroxy-5alpregnane-1,1,20-dione (500 mg.) in pyridine (2.5ml.) was treated with propionic anhydride (2.5 ml), and the solution wasleft at room temperature overnight. Water was added, and the mixture wasextracted with chloroform. The extract was washed with dilutehydrochloric acid, dired over sodium sulphate and evaporated to an oilwhich was purified by preparative tlc to give the title compound (295mg.) as a colourless foam [11],, 107.

EXAMPLE 39 2/3-Methoxy-3a-trifluoroacetoxy-5 a-pregnane-l l,20- dioneEXAMPLE 4'0 3oz-Acetoxy-2B-bromo-Sa-pregnane-l l,20-dione2,8-Bromo-3a-hydroxy-5oz-pregnane-l l ,20-dione (750 mg.)-in pyridine (2ml.) was treated with acetic anhydride (1 ml.) and the mixture wasallowed to stand at room temperature overnight. It was then poured intowater to give a white solid (720 mg.) which was recrystallised frommethanol to give the title compound (471 mg.) as white crystals, m.p.l54156, [111 l28.5.

EXAMPLE 41 B, l6oz-Dichloro-3a-hydroxy-5a-pregnane-l l,20-dione 2a,3a-Epoxy-5a-pregn-16-ene-l l,20-dione (600 mg.) in chloroform (25 ml.) wasshaken with concentrated hydrochloric acid (25 ml.) for 2 hours. Theorganic layer was washed with water, dried over sodium sulphate andevaporated to an oil which was purified by preparative tlc to give2,8-chloro-3a-hydroxy-5apregn-l6-ene-l l,20-dione as the major product.Also isolated was the title compound mg.) as fine white crystals, m.p.l92-l94, [04],, 98.

EXAMPLE 42 23,16oz-Dichloro-3a-hydroxy-5a-pregnane-l l,20- dione2a,3a-Epoxy-5a-pregn-l6-ene-1 l,20-dione (660 mg.) was dissolved indioxan (40 ml.) and the solution was saturated with dry hydrogenchloride. After 2 hours, the solution was poured into water and theprecipitate extracted into chloroform. Th'eextract was washed withwateruntil the washings were neutral, dried over sodium sulphate andevaporated to a foam which was purified by preparative tlc andrecrystallisation from ethylacetate/petrol to give the title compound(426 mg.) as colourless needles. mp 192|96, [01],, 98.

EXAMPLE 43 Reaction of 2a,3a-Epoxy-5a-pregnane-l 1,20-dione withChloroacetic Acid in Terahydrofuran.

Chloroacetic acid (8 g.) was dissolved in dry tetrahydrofuran (8 ml.) at50-55 and to the stirred solution was added 2a,3a-epoxy-5a-pregnane-1 1,20-dione (1.0 g. The reaction solution was stirred at 50 for 4 hours.The reaction mixture was diluted with ice-cold water (50 ml.) andextracted with chloroform (2 X 50 ml.). The extract was washed withdilute potassium bicarbonate solution and with water, dried over sodiumsulphate and evaporated toan oil (about 1.3 g.) which was purified bypreparative tlc on 120 g. of silica in ethyl acetate/petroleum etherl/l, run 3 times, the two closely running major bands being separated.The

upper band (R, 0.35-0.45) yielded ZB-chloroacetoxy- 3ahydroxy-5a-pregnane-l120-dione (307 mg.) as a white foam, [01],, 79.0(c085).

The lower band from the tlc plates (R 0.15-0.35) yielded2B-(4-chloroacetoxy-n-butoxy)-3a-hydroxy- Sti prEgflari'e ll'fiidicin'e(735' mans anaemia foam which collapsed to a gum on standing,[01],, 690 0.68).

EXAMPLE 44 2B-Chloroacetoxy-3a-hydroxy-Sa-pregnane-l 1.20- dione a. Asolution of chloroacetic acid (g) in benzene (40 ml.) was refluxed undera Dean and Stark head for minutes. 2a,3a-Epoxy-5a-pregnane-ll,20-dione1(l g.) was added and reflux continued for a further 2 hours.Ether (40 ml.) was added to the cooled solution and the organic mixturewashed with sodium bicarbonate solution until effervescence had ceased.The organic layer was washed with water (2 X 100 ml. dried overanhydrous sodium sulphate and evaporated in vacuo to a pale yellow foam(1.29 g.) which was chromatographed on a silica (50 g.) column usingchloroform as eluant. Fractions 4-12 (50 ml. each) gave the titlecompound (500 mg.) as a white foam.

Fractions 1 and 2 were purified by preparative tlc usingchloroform/ethyl acetate l/l to give2B,3a-di-(-chloroacetoxy)-5a-pregnane-l1,20-dione (330 mg.) as a whitefoam. [01],, 91.5".

b. Similarly, using the same amounts of the various reagents as in (a)above with the reaction mixture maintained at a temperature of 50 for 5hours and after isolation as in (a) above gave the title compound (900mg).

EXAMPLE 45 3a-Hydroxy-2,B-iodoacetoxy-5awpregnane-l1,20-dioneZfi-Chloroacetoxy-3a-hydroxy-5a-pregnane-1 1,20- dione (300 mg.) wasdissolved in acetone (30 ml.). Sodium iodide (310 mg.) was added and themixture refluxed for 40 minutes, a crystalline solid precipitating inthis time- The solid was filtered off and the filtrate evaporated to apale green solid which was partitioned between ether/water. The organiclayer was dried over anhydrous sodium sulphate and evaporated in vacuoto give the title compound as an off-white foam (325 mg.) [01] 67 (01.01).

EXAMPLE 46 ZB-N,N-Diethylaminoacetoxy-3a-hydroxy-5apregnane-ll',20-dione 3a-Hyd roxy-ZB-iodoacetoxy-Sa-pregnane-l 1,20- dione (385mg.) was dissolved in dried methylene chloride (30 ml.) and diethylamine(1 ml.) added to the stirred solution. The mixture was stirred at roomtemperature for 40 minutes. Methylene chloride (50 ml.) was added andthe mixture was washed with water ml.), dried over anhydrous sodiumsulphate and evaporated to an orange oil (345 mg.) which was purified bypreparative tlc in acetone to give the title compound (290 mg.) as awhite foam. [01],, 72.9 (c 0.94).

EXAMPLE 47 3a-Hyd roxy-ZB-morpholinoacetoxy-5a-pregnanel 1,20-dione3a-Hydroxy-2B-iodoacetoxy-Sa-pregnane-1 1,20- dione (578 mg.) wasdissolved in dried methylene chloride and morpholine (1 ml.) was addedto the solution. The mixture was stirred at room temperature for onehalfhour, a white precipitate forming. The mixture was filtered and thefiltrate evaporated in vacuo to a yellow oil (340 mg.) which waspurified by preparative tlc in ethyl acetate run twice to give thetitlecompound (200 mg.) as a white foam. [01],, 65 (c 0.48).

EXAMPLE 48 3a-Hydroxy-2B-piperidinoacetoxy-Sa-pregnanel 1,20-dione3oz-Hydroxy-ZB-iodoaetoxy-Sa-pregnane-l 1.20-

dione (550 mg.) was dissolved in methylene chloride (25 ml.) andpiperidine (1 ml.) added to the solution. The mixture was stirred atroom temperature for 1 hour. The solution was evaporated to a paleyellow solid which was partitioned between ether/water. The organiclayer was dried over anhydrous sodium sulphate and evaporated to a whitefoam (460 mg.) which was purified by preparative tlc inacetone/petroleum ether 1/1. The main band (R 0.4-0.5) gave the titlecompound (420 mg.) as a white foam. [01],, 80.4 (c 0.99).

EXAMPLE 49 a-liiqr zsyzzitiqasswyrmbqt wpregnane-l 1,20-dione2B-(4'-Chloroacetoxy-n-butoxy)-30z-hydroxy-5apregnane-l 1,20-dione (450mg.) was dissolved in acetone (30 ml.) and sodium iodide (460 mg.) addedto this solution. The mixture was refluxed for 1 hour, a whiteprecipitate forming in this time. The mixture was filtered and thefiltrate evaporated to a yellowish solid which was partitioned betweenether and water. The ethereal solution was dried over anhydrous sodiumsulphate and evaporated in vacuo to give the title compound (467 mg.) asa pale yellow foam which almost immediately collapsed to a gum. Thisunstable product was used immediately for the following Examples 50 and51 EXAMPLE 50 3a-Hydroxy-2B-(4'-morpholinoacetoxy-n-butoxy )5apregnane-l 1,20-dione3a-Hydroxy-2,B-(4'-iodoacetoxy-n-butoxy)-5apregnane-l 1,20-dione (467mg.) was dissolved in dried methylene chloride (30 ml.) and morpholine(1 ml.) added to this solution. The mixture was stirred at roomtemperature for l hour, a white precipitate forming in this time. Themixture was filtered and the filtrate evaporated to a yellow oil whichwas purified by preparative tlc in ethyl acetate (run twice) to give thetitle compound (220 mg.) as a colourless oil. [01], 57.l (c 0.49).

EXAMPLE 51 2,8-(4'N,N-Diethylaminoacetoxy-n-butoxy)-3ahydroxy-Sa-pregnane-l 1,20-dione3a-Hydroxy-2B-(4'-iodoacetoxy-n-butoxy)-5apregnane-l l ,20-dione (355mg.) was dissolved in dried methylene chloride (30 ml.) anddiethyl'amine (1.5 ml.) added to the stirred solution. The mixture wasstirred at room temperature for 1 hour. Methylene chloride was added andthe solution washed with water (2 X 100 ml.). dried over anhydroussodium sulphate and evaporated to an orange oil (400 mg.) which waspurified by preparative tlc in ethyl acetate to give impure titlecompound (260 mg.).

EXAMPLE 52 2,8-( 4-H yd roxy-n-butoxy )-3u-hydroxy-5oz-pregnanel1,20-dione 2,8-(4'-Chloroacetoxy-n-butoxy)-3a-hydroxy-5oipregnane-ll,20-dione (380 mg.) was dissolved in methanol (40 ml.) and the stirredsolution heated to 50C. Perchloric acid (0.5 ml.) was added and themixture stirred at 50C for 5 hours. The mixture was neutralised withsodium bicarbonate solution, poured into water and extracted wtih ether(2 X 100 ml.). The combined extracts were washed with water (200 ml.),dried over anhydrous sodium sulphate and evaporated in vacuo to a whitefoam (270 mg.) which was purified by preparative tlc inacetone/petroleum ether l/l to give the title compound (l70 mg.) 110+79.5

EXAMPLE 53 Reaction of 2a,3a-epoxy-5a-pregnane-l l.20-dione withZ-bromoethanol 2a,3a-Epoxy 5a-pregnane-l1,20-dione (660 mg.) wasdissolved in ether (70 ml.) and 2-bromoethanol (1 ml.) added to thesolution. Concentrated sulphuric acid (0.5 ml.) was then added and themixture stirred at room temperature for one-half hour. Potassiumbicarbonate solution (18 ml.) was added and when effervescence hadceased the aqueous layer was removed and extracted with ether (20 ml.).The combined organic extracts were washed with water (100 ml.), driedover anhydrous sodium sulphate and evaporated in vacuo to a pale yellowoil (794 mg.) which was purified by preparative tlc. The main band (R0.3) gave 23- bromo-3a-hydroxy-Sa-pregnane-l 1,20-dione (230 mg.), mp.l72-3C identical with a previously prepared sample.

EXAMPLE 54 2B( 2-Chloroethoxy)-3a-hydroxy-Sa-pregnane-l 1,20- dione2a,3a-Epoxy-5a-pregnane-l1,20-dione (l g.) was dissolved in2-chloroethanol (50 ml.) and concentrated sulphuric acid (six drops)added to the solution. The mixture was stirred at room temperature for 1hour. neutralised with sodium bicarbonate solution and poured into water(500 ml.). The precipitate formed was extracted into other (2 X 100 ml.)and the combined extracts washed with water (2 X 100 ml.). The organiclayer was dried over anhydrous sodium sulphate and evaporated to ayellow oil 1.5 g.) which was purified by preparative tlc using ethylacetate/petroleum ether, l/l run 3 times. The main band (R -0.2-0.3)gave the title compound (640 mg.) as an off-white foam identical with apreviously prepared sample.

The second major band (R,--0.35) gave 2,8-chloro-3a-hydroxy-5a-pregnane-l1,20-dione (205 mg.) as a white crystallinesolid, mp. l-l 89C, identical with an authentic sample.

EXAMPLE 55 3a-Hydroxy-2,B-( 2 -morpholinoethoxy )-5a-pregnane- 11,20-tlione EXAMPLE 56 2/3-( 2 '-Chloroethoxy )-20,20-ethylenedioxy- 3ahydroxy-Sa-pregnan-l l-one 2,B-(2-Chloroethoxy)-3a-hydroxy-5a-pregnanell, 20-dione (600 mg.) was dissolved in benzene (50 ml.),ethylene glycol (5 ml.) and toluene-p-sulphonic acid (2 mg.) added, andthe vigorously stirred mixture refluxed under a Dean and Stark head for20 hours.

The cooled mixture was washed with sodium bicarbonate solution (5 ml.),water (2 X ml.) and dried over anhydrous sodium sulphate. The driedsolution was evaporated in vacuo to give the title compound (605 mg.) asa pale yellow foam, [01],, 47.2 (c. 1.1 1).

EXAMPLE 57 3a-l-lydroxy-2B-(2-morpholinoethoxy) Sa-pregnanel l,20'dione2B-(2-Chloroethoxy)-20,20-ethylenedioxy-3ahydroxy-Sa-pregnan-l l-one(500* mg.) was dissolved in morpholine (15 ml.) and the solution heatedon a steam-bath for 24 hours. The morpholine was removed by evaporatingin vacuo and the resulting red oil was 7 dissolved in 35% aqueous aceticacid (25 ml.). This solution was heated on a steam-bath for 2 /2 hours.Water (50 ml.) was added and the slightly turbid solution filteredthrough Kieselguhr. The filtrate was made alkaline with ION-potassiumhydroxide and the precipitate extracted into ether (100 ml.). The etherextract was washed with water until the aqueous layer was neutral,

dried over anhydrous sodium sulphate and evaporated to give the titlecompound as a white foam (250 mg.) [a],, 82 (c 0.98).

EXAMPLE 58 2B-( 3 '-Chloropropoxy)-20,20-ethylenedioxy-3ahydroxy-Sa-pregnan-l l-one2B-(3'-Chloropropoxy)-3a-hydroxy5a-pregnane- 11,20-dione (470 mg.) wasadded to a mixture of ethylene glycol (4 ml.), toluene-p-sulphonic acid(3 mg.) and benzene (50 ml.). The vigorously stirred mixture wasrefluxed under a Dean and Stark head for 17 hours. The cooled mixturewas neutralised with sodium bicarbonate solution, ether (50 ml.) addedand the organic mixture was washed with water (250 ml. The organicsolution was dried over anhydrous sodium sulphate and evaporated to givethe title compound (520 mg.) as a white foam, [04] -1- 37.5 (C 1.03).

EXAMPLE 59 3a-Hydroxy-2/3-( 3 '-morpholinopropoxy )-5apregnane-l1,20-dione2,8-(3'-Chloropropoxy)-20,20-ethylenedioxy-3ahydroxy-Sa-pregnan-ll-one(500 mg.) was dissolved in morpholine (5 ml.) and the solution heated ona steambath for 8 hours. The solution was poured into water and theprecipitate extracted into ether (70 ml.). The ethereal solution waswashed with water, dried over anhydrous sodium sulphate and evaporatedto a white foam (480 mg.) which was dissolved in 35% aqueous acetic acidand the solution heated on a steambath for 3 hours. The solution wascooled in ice and an ice-cooled solution of ION-potassium hydroxideadded to the stirred solution in the presence of ether (100 ml.) untilthe aqueous layer was basic. The aqueous layer was extracted with ether(50 ml.) and the combined ether extracts washed with water, dried overanhydrous sodium sulphate and evaporated to a white foam (390 mg.) whichwas purified by preparative tlc in acetone to give the title compound(250 mg.) as a white foam, [a],, 650 (c 1.02).

EXAMPLE 60 3a-Hydroxy-ZB-piperidinoacetoxy-Sa-pregnanel 1,20-dione,citrate salt 3a-Hydroxy-2/3-piperidinoacetoxy-5a-pregnane- 11,20-di0ne(95 mg.) was dissolved in ethanol (2 ml.) and to the solution was added0.1 molar aqueous citric acid solution (2 ml.). The mixture wasevaporated at 40", and the residue was dried in vacuo to constantweight. Water (2 ml.) was added, and the mixture was filtered. The solidwas washed with water (2 ml.), then dissolved in chloroform and thesolution evaporated and dried in vacuo to give a white solid (10 mg.).It was therefore assumed that the aqueous filtrates contained.

85 mg. of the steroidal base, and so these were combined and dilutedwith water to 8.5 ml to give a concentration of 10 mg./ml. with respectto steroid free base.

EXAMPLE 61 ZB-Ethoxy-Ba-hydroxy-l 9-nor-5a-pregnane-l 1,20- dione Astirred solution of 3oz-hydroxy-l9-nor-5apregnane-11.20-dione (1.0 g.)in dry pyridine (5 ml.) was treated with toluene-p-sulphonyl chloride(1.0 g.) overnight at room temperature. The resulting solution waspartitioned between water (100 ml.) containing 2- 24 N-hydrochloric acid(12 ml.) and chloroform. The organic layer was washed, dried (Na SO andevapo' rated to afford the crude tosylate (1.2 g.).

A solution of the crude tosylate in benzene (35 ml.) was run onto gradeH alumina and left overnight. Elution of the column with benzene andevaporation of the solvent afforded crude l9-norl5a-pregn 2-ene-l1,20-dione (0.58 g.).

a solution of crude 19-norl5a-pregnl2-ene-l1,20- dione (0.58 g.) inethanol free chloroform (8 ml.) was treated with m-chloroperbenzoic acid(0.5 g.) overnight at room temperature. The resulting solution waspartitioned between chloroform and dilute aqueous sodium bicarbonate.The organic layer was washed. dried (Na SO and evaporated to affordcrude 2a, 301- epoxy-19-nor-5a-pregnane-11,20-dione (0.7 g.).

A solution of crude 2oz, 3a-epoxy-19-nor-5apregnane-l 1,20-dione (0.7g.) in ethanol (30 ml.) was treated with concentrated sulphuric acid (2drops.) at room temperature for 15 min. The resulting mixture waspartitioned between water and ether and the organic layer was washedwith water, dried (Na SO and evaporated. The residue was subjected topreparative tlc (EtOAc:CHCl l:3) to afford the title compound (0.2 g.)as a white foam; (al 162 (c 0.6).

EXAMPLE 62 2B-n-Butyl-3a-hydroxy-5 oz-pregnane- 1 1,20-dione A 2 molarsolution of n-butyl lithium in hexane (30 ml, 60 mmole) was added to astirred suspension of cuprous iodide (5.7 g., 30 mmole) in dry ether (90ml.) under nitrogen at 20. A cold solution pf 2a, 304-epoxy-Sa-pregnane-l1,20-dione (1.65 g., 5 mmole) in dry ether (260 ml.)was then added and the mixture was maintained at 0 for hr. The reactionmixture was then poured into aqueous ammonium chloride solution andextracted into ethyl acetate.

The organic extract was washed with water, dried (MgSOQ and evaporatedin vacuo. The residue (2.23

g.) was purified by repeated preparative thin layer chromatography togive the title compound (0.21 g.). [01],, l02.5 (c 0.5).

EXAMPLE 63 2B-Acetoxy-3a-hydroxy-Sa-pregnane-1 1,20-dione 2a,3a-Epoxy-5a-pregnane-l1,20-dione (500 mg.) was dissolved in glacialacetic acid (25 ml. and the solution was heated on a steam-bath for 3hours. Evapo ration of the solution under reduced pressure gave an oilwhich was purified by preparative tlc in ethyl acetate-petrol, andfoamed in vacuo to give the title compound as a white foam, [01],,93.5".

EXAMPLE 64 3a-Acetoxy-2B-bromo-Sa-pregnan-ZO-one A solution of3a-hydroxy-2B-bromo-5a-pregnan- 20-one (8.5 g.) in pyridine (25 ml.) wastreated with acetic anhydride (12.5 ml.), and the mixture was allowed tostand at room temperature overnight. The reaction mixture was pouredinto water and the product was extracted with methylene chloride. Theextract was. washed with water, dried (Na SO and evaporated. A

portion (582 mg.) of the residue (8.5 g.) was purified by preparativethin layer chromatrography and crystallisation from iso-propyl ether togive the title compound (70 mg.). mp l42l46, [01],, 120.9.

EXAMPLE 65 2B-Ethoxy-3a-hydroxyl 6a-methyl-5 a-pregnanel 1,20-dione Asolution of methyllithium in ether (c, 2M 4 ml.) was added to a stirredslurry of cuprous iodide (630 mg.) in dry ether (60 ml.) under drynitrogen until the initially formed yellow precipitate redissolved. Asolution of ZB-ethoxy-3a-hydroxy-5a-pregnl6-ene-l 1,20-dione (420 mg.)in dry tetrahydrofuran (35 ml.) was added to the stirred solution at andstirring was continued, at 0, for 30 minutes. The mixture was thenpoured into saturated ammonium chloride solution (150 ml), more ether(150 ml.) was added, the organic layer separated, washed with saturatedammonium chloride solution (150 ml.) and water (150 m1.) and dried (NaSO The solution was then evaporated. The residue was purified bypreparative TLC (CHCl X 4). The least polar component was recrystallisedfrom acetone/petrol to give title compound (130 mg.) as white needles;mp. 178179; [01] 112 (c 0.3).

EXAMPLE 66 2/3-(Z-Cyanoethoxy)-3a-hydroxy-Sa-pregnane-1l,20 dione 2a,3a-Epoxy-5oz-pregnane-l1,20-dione (2 g), dry ether (50 ml) and2-cyanoethanol 10 ml.) were stirred at room temperature until the solidhad dissolved. Boron trifluoride diethyl etherate (10 drops) was added.After 2 hours at room temperature a further quantity of etherate (10drops) was added. After 1 hour furtheretherate (10 drops) was added andafter a further hour, the mixture was neutralised with saturated sodiumbicarbonate solution, ethyl acetate (50 ml.) added and the organic layerwashed with water (3 X 200 ml.). The washed solution was dried overanhydrous sodium sulphate and evaporated to a white foam which waspurified by preparative tlc using ethyl acetate. The main band (Rf 0.4)gave the title compound (740 mg;) mp. l94196C, [611 85.

EXAMPLE 67 2B-( 2-Ethoxycarbonylethoxy)-3a-hydroxy-5apregnane-l1,20-dione 2B-(Z-Cyanoethoxy)-3a-hydroxy-5a-pregnane- 11,20-dione (430mg.) was dissolved in absolute ethanol (50 ml) and dry hydrogen chloridepassed through the solution until saturation occurred. The mixture wasleft for one-quarter hour then poured into water (250 ml.). Afterone-half hour the precipitate formed was extracted into ether (2 X 100ml), the ethereal solution washed with water and dried over anhydroussodium sulphate.

The dried solution was evaporated to a white foam (320 mg) which waspurified by preparative tlc using ethyl acetate/petrol (4/1) run twice.The main band (RF-0.4) gave title compound (140 mg) as an oil. [01],,

EXAMPLE 68 3a-Hydroxy-ZB-propiomyloxy-Sa-prepnane-l 1.20- dione 2a,3a-Epoxy-5a-pregnane-l1.20dione (500 mg) was dissolved in propionic acid(10 ml) and the solution heated on a steam bath for 5 hours. The mixturewas poured into water (200 ml) and the white precipitate extracted intoether. The ethereal solution was washed with 2N-sodium hydroxidesolution until the aqueous layer remained basic, then water and thendried over anhydrous sodium sulphate. The dried solution was evaporatedto a white foam (560 mg) which was purified by preparative tlc usingethyl acetate/petrol (2/1). The main band (Rf 0.4-0.5) gave titlecompound (393 mg.) as a white foam. [01],, 84.4(c 1.05).

EXAMPLE 69 3a-Hydroxy-2B-toluene-p-sulphonyloxy-5oz-pregnanel 1,20-dioneToluene-p-sulphonic acid (550 mg) was refluxed in benzene (20 ml) undera Dean and Stark head for onehalf hour. The solution was cooled to roomtemperature, the acid crystallising out, ether (20 ml) added and themixture stirred until the crystals had redissolved. A mixture of2a,3a-epoxy-5a-pregnane-l 1,20-dione (1. g) and ether 10 ml) was addedand the reaction stirred at room temperature for 14 hours. The mixturewas poured into water, the organic layer separated and the aqueous layerextracted with ether (50 ml). The combined organic extracts were washedwith sodium bicarbonate solution, water (100 m1) and dried overanhydrous sodium sulphate. The dried solution was evapr rated to givetitle compound (1.32 g) as a white foam, [04] 52 0 0.94).

EXAMPLE 70 2B-Azido-3a-hydroxy-5a-pregnane-l 1,20-dione a.2oz,3a-Epoxy-5a-pregnane-l1,20-dione (500 mg) was dissolved indimethylsulphoxide (25 ml) and sodium azide (1.5 g) added to thesolution. Concentrated sulphuric acid (10 drops) was added and themixture heated on a steam bath for 48 hours. The solution was pouredinto iced water (600 ml) and the precipitate extracted into ether ml)The ether extract was washed with water (4 X 250 ml) and then saturatedsodium bicarbonate solution (250 ml) and finally water (250 ml.). Theorganic solution was dried over anhydrous sodium sulphate and evaporatedto a white foam which was purified by preparative TLC using ethylacetate/petrol (l/l) run twice. The main band gave title compound (290mg;) as a foam, [04],, 95 (0, 0.98

b. 2a,3a-epoxy-5a-pregnane-l1,20-dione (1 g) was added to a mixture ofsodium azide (lg), boric acid (1g) and dimethylformamide (20 ml) and themixture refluxed for 5 hours. The mixture was cooled, poured into waterand the resulting emulsion extracted into methylene chloride (2 X ml.).The organic extracts were washed with water (2 X 300 ml.) dried overanhydrous sodium sulphate and evaporated to a red oil which was purifiedby preparative TLC using ethyl acetate/petrol (l/l the main band givingZB-azido- 3a-hydroxy-5a-pregnane-l1,20-dione (580 mg) as a foam.

3a-hydroxy-2B-toluene-p-sulphonyloxy-Sapregnane-ll,20-dione (500 mg) wasdissolved in dimethylsulphoxide (20 ml) and sodium azide (1.5 g) addedto the solution. The mixture was heated on a steam bath for 30 hours.cooled and poured into water.

The precipitate formed was filtered off. dissolved in ether and thesolution dried over anhydrous sodium sulphate. The dried solution wasevaporated to a foam 27 (300 mg) which was purified by preparative TLCusing ethyl acetate/petrol (1/1). The main band (Rf 0.2-0.3) givingtitle compound (200 mg) as a foam, [a] 104 (c 0.93), identical with theabove compound.

EXAMPLE 71 2B-Ethoxy-3a-hydroxy-5a-pregnane-1 l.20-dione,3-hemisuccinate Succinic anhydride (220 mg.) was added to a solution of2/3-ethoxy-3a-hydroxy-5a-pregnane-l 1,20- dione 220 mg.) in dry pyridine(2.2 ml.). The stirred solution was refluxed gently (oilbath temperature130) for 5 hours, and then poured into water ml. The mixture wasacidified with dilute hydrochloric acid and extracted with chloroform.The extract was washed with water, dried over sodium sulphate andevaporated to an oil which was purified by preparative tlc in ethylacetate to give title compound (129 mg) as a foam which collapsed to agum on standing, [01],, 89 (c 0.41).

EXAMPLE 72 3a-N,N-Diethylaminoacetoxy-ZB-ethoxy-Sa-pregnanel 1,20-dione2B-Ethoxy-3a-hydroxy-5a-pregnane-l 1,20-dione (l g) was dissolved inmethylene chloride (5 ml) and pyridine (1 ml.). Chloroacetic anhydride(1 g) was added to the solution and the mixture left at room temperatureovernight, the solution becoming deep red and containing a brownprecipitate. The mixture was poured into water, methylene chloride addedand the organic layer washed with very dilute sulphuric acid, water anddried over anhydrous sodium sulphate. The dried solution was evaporatedto a yellow foam which was chromatographed on a'silica g) column usingchloroform, the first 150 ml. containing 301-Chloroacetoxy-2,B-ethoxy-5a-pregnane-1 1,20-dione (910 mg.) as a whitefoam.

3a-Chloroacetoxy-ZB-ethoxy-Sa-pregnane-11,20- dione (450 mg) wasdissolved in acetone (50 ml) and sodium iodide (460 mg) added to thesolution. The mixture was refluxed for one-half hour, a whiteprecipitate forming. The precipitate was filtered off and the filtrateevaporated to a yellow foam which was partitioned between ether andwater. The ethereal solution was dried over anhydrous sodium sulphateand evaporated to give ZB-ethoxy-3a-iodacetoxy-5oz-pregnane- 11,20-dione(460 mg) as a pale yellow foam.

2,8-Ethoxy-3a-iodoacetoxy-5a-pregnane-11,20-

dione (460 mg) was dissolved in methylene chloride (25 ml) anddiethylamine (1 ml) added to the solution. The mixture was stirred atroom temperature for onehalf hour. The mixture was poured into water andthe organic layer washed with water (100 ml.), dried over anhydroussodium sulphate and evaporated to a red oil (410 mg.) which was purifiedby preparative tlc using ethyl acetate/petrol (2/1) run twice. The mainband (Rf0.4) gave title compound (230 mg) as a pale yellow oil [01], 100(c 0.9).

EXAMPLE 73 3a-Hydroxy-2B-methoxy- 1 6,B-methyl-5 a-pregnanel 1.20-dione3a-Hydroxy-2B-methoxy-16-methyl-5a-pregnl6-ene-11,20-dione(187 mg.) inethyl acetate (50 ml.) was hydrogenated over 10% palladium-on-carboncata- EXAMPLE 74 2B-Acetylthio-3a-hydroxy-Sa-pregnane-l 1,20-dione2a,3a-Epoxy-Sa-pregane-l1,20-dione (450 mg.) in dry ether (4 ml.) andthioacetic acid (1 ml.) was treated with BF etherate (two drops). Theresulting yellow solution was stirred at room temperature for 20minutes. The solution was partitioned between ethyl acetate (20 ml.) andwater (20 ml.) and the aqueous layer was extracted with more ethylacetate (20 ml.). The combined organic extracts were washed with water(2 X 20 ml.) and dried over sodium sulphate and evaporated to a yellowoil which was purified by preparative tlc, in ethyl acetate/petroleumether (11-1) to give the title compound as a pale yellow foam. [01] 93(c 0.56); R 015; N.M.R.:7.65r (CH COS); 6.167 (2- and 3-H).

EXAMPLE 75 0.011 of 3a-hydroxy-ZB-methoxy-Sa-pregnane- 11,20-dione weredissolved in 2 ml. of acetone at 20C. The resulting solution was addedto l g. of Cremophor EL at 20C. and stirred until homogeneous. Theacetone was removed by a vigorous stream ofnitrogen. The solution wasdiluted with sterile distilled water containing 0.025 g. of sodiumchloride to give a final volume of 5 ml.

EXAMPLE 76 0.028 g. of 2B,3a-dihydroxy-5a-pregnane-1 1,20- dione weredissolved in 2 m1. of acetone at 20C. The resulting solution was addedto l g. of Cremophor EL at 20C. and stirred until homogeneous.

The acetone was removed by a vigorous stream of nitrogen. The solutionwas diluted with sterile distilled water containing 0.025 g. of sodiumchloride to give a final volume of 5 ml.

EXAMPLE 77 0.0148 g. of 2B-chloro-3a-hydroxy-Soz-pregnane- 11.20-dionewere dissolved in 2 ml. of acetone at 20C.

The resulting solution was added to l g. of Cremophor EL at 20C. andstirred until homogeneous. The acetone was removed in a vigorous streamof nitrogen. The solution was diluted with sterile distilled watercontaining 0.025 g. of sodium chloride to give a final volume of 5 ml.

The following preparations illustrate the preparation of startingmaterials used in preparing certain compounds according to theinvention.

Preparation 1.

2a, 3a-Epoxy-5a-pregn-16-ene-1 1,20-dione To a. solution of5a-pregna-2,l6-diene11,20-dione (2.5 g.) in chloroform (50 ml.) wasadded mchloroperoxybenzoic acid 1.8 g), and the mixture was stirred atroom temperature overnight. More chloroform was then added, and thesolution was washed with dilute sodium bicarbonate solution and withwater, dried over magnesium sulphate and evaporated to an oil which wastriturated with ether/petrol to give title compound (1.9 g.) ascolourless needles, m.p. l54-l56, [th, 100.

Preparation 2.

' as colourless prisms, m.p. 209"2l2 (decomp.), [01],,

+ 83, A 234 nm (6 8,350) (EtOH).

Preparation 3.

3a-Hydroxy-2B-methoxy-5a-pregnl6-ene-1 1,20- dione2a,3oz-Epoxy-5a-pregn-l 6-ene-l 1,20-dione (500 mg.) was dissolved inmethanol (25 ml.) and to the stirred solution was added concentratedsulphuric acid (0.1 ml).

The solution was stirred at room temperature for 15 minutes, then 10%potassium bicarbonate solution ml.) was added, and the mixture waspoured into water. The precipitate was extracted into chloroform, andthe extract was dried over sodium sulphate and evaporated to an oilwhich was recrystallised from ethyl acetate/petrol to give titlecompound (370 mg.) as fine white crystals, m.p. 159l63, [11],, 82.0".

Preparation 4 2a, Sa-Epoxy-Sa-pregn-l6-en-20-one a.3B-Toluene-p-sulphonyloxy-Sa-pregn-l6-en- 20-one3B-Hydroxy-5a-pregn-l6-en-20-one g.) in pyridine (50 ml.) was treatedwith toluene-p-sulphonyl chloride (10 g.), and the solution was stirredat room temperature overnight and then poured into dilute hydrochloricacid. The precipitate was extracted into chloroform, and the extract waswashed with dilute hydrochloric acid and with water, dried over sodiumsulphate and evaporated to an oil which crystallised on standing.Recrystallisation from ethyl acetate/petrol gave3Btoluene-p-sulphonyloxy-Sa-pregn-l 6-en- -one (13.3 g) as off-whiteprisms, m.p. l46-l48, [01] 24.0, A,,,.,, (EtOH) 226.5 nm (el8,600), 240nm (infL) (59550), 272.5 nm (6518).

b. 5a-Pregna-2,l6-dien-20-one 3B-Toluene-p sulphonyloxy-S oz-pregnl6-en-20-one (6 g.) was added to hot collidine 12 ml.), and the solutionwas then refluxed for 30'minutes. The solution was allowed to cool andthen poured into cold dilute hydrochloric acid. The precipitate wasfiltered off, washed with water and dissolved in methylene chloride. Thesolution was dried over sodium sulphate and then filtered through ashort column of silica gel (50 g.). The methylene chloride eluate (about150 ml.) was evaporated to give 5a-pregna-2,l6-dien-20-one (3.29 g.) aswhite crystals, m.p. l43-l45. [011 ll0.5.

c. 20:, 3a-Epoxy-5a-pregn-l6-en-20-one 5aPregna-2,l6-dien-20-one (3.0g.) in chloroform (50 ml.) was treated with m-chloroperbenzoic acid 2.0g.). The solution was stirred at room temperature overnight, dilutedwith more chloroform (50 ml.), washed with dilute potassium bicarbonatesolution and with water, dried over sodium sulphate and evaporated to anoil which crystallised on standing. Recrystallisation from ethylacetate/petrol gave title compound (2.75 g.) as colourless plates, m.p.l45-l49 [(11 74.5, A 23lB nm (8970).

Preparation 5 2B-Chloro-3a-hydroxy-5a-pregnl 6-en-20-one 2a,Ba-Epoxy-Soz-pregml6-en-20-one (500 mg.) was dissolved in methylenechloride (15 ml.) and concentrated hydrochloric acid (12 ml.) was added.The mixture was shaken for 20 minutes, and then poured into water ml.)and chloroform l00 ml.). The organic layer was separated, washed wellwith water, dried over sodium sulphate and evaporated to an oil.Recrystallisation from ethyl acetate gave title compound (447 mg.) ascolourless crystals, m.p. 246-252, [a],,(c, l.10)+ 65.8", h (EtOH) 239nm (8770).

Preparation 6 I 3oz-Hydroxy-2B-methoxy-5oz-pregn-l 6-en-20-one 2oz,3a-Epoxy-5a-pregnl6-en-20-one (500 mg.) in methanol (30 ml.) was treatedwith concentrated sulphuric acid (0.] ml.). The reaction solution wasstirred at room temperature for 10 minutes, and then potassiumbicarbonate solution (10, 6 ml.) and water were added and theprecipitate was extracted into chloroform. The chloroform solution wasevaporated to an oil which was purified by preparative tlc in ethylacetate/- petrol (1/2), to give, as the major product title compound(255 mg) as colourless plates (from ethyl acetate/petrol), m.p. l86-l89,[01],, (c, 0.82) 62, k (EtOH) 239 nm (68370).

Also isolated was 213, 16a, -dimethoxy-3a-hydroxy- 5a-pregnan-20-one (42mg.) as colourless needles (from ethyl acetate/petrol). m.p. l83-l87.

Preparation 7 a. 3B-Hydroxy-5a-pregn-l6-ene-l l,20-dione A solution ofBB-acetoxy-Sa-pregn-l6-ene-l1,20- dione (Chamberlin et al., J. Amer.Chem. Soc, 1951, 73, 2396) (25.7 g.) in dioxan (500 ml.) was treatedwith potassium hydroxide (10 g.) and water 250 ml. and the mixtureallowed to stand at room temperature for l hour. After a further 1 hourat 40 the mixture was diluted with water and the product filtered off.The crude material was dissolved in chloroform and filtered through acolumn of grade III neutral alumina (ca. 100 g.). The material obtainedwas crystallised from acetone petroleum togive pure title compound(17.65 g.), as small plates, m.p. 217.5", [04],, 82.9 (c l.l), M 234 nm.(6 10,100).

b. 3B-Toluene-p-sulphonyloxy-5a-pregn-l6-ene-l 1,20- dione A solution of3B-hydroxy-5a-pregn-l6-ene-l1,20-- dione (39.6 g) in dry pyridine (1.65ml.) was treated with toluene-p-sulphonyl chloride (43.9 g.) to give thetoluene sulphonate (56.7 g.) m.p. l47-15 1. A portion (l0.7 g.) of thismaterial was crystallised from ethyl acetate-petroleum to give the puretoluene sulphonate (9.2 g.) as plates m.p. l54l55, [01] 428 (c, 1.2).h,,,,,,. 226 nm (a 20,780).

c. 3a-Hydroxy-5wpregn-l6-ene-l1,20-dione and 5apregna-2, 1 6-diene-11,20-dione A stirred mixture of3B-toluene-p-sulphonyloxy-5ozpregn-l6-ene-1 1,20-dione (627 g.),potassium acetate (918 g.),'dimethylformamide (4.25 l.) and water (425ml.) was heated on the steam bath for 4 hr. Most of thedimethylformamide was removed under reduced pressure and water was addedto the residue with stirring. The solid (420 g.) was collected, washedand dried at 40 in vacuo. This material in peroxide free dioxan (7 l.)was flushed with nitrogen and a solution of potassium hydroxide (200 g.)in water (2 1.) was added. The mixture was stirred and heated at 5060for 7 hr. and then left at room temperature overnight. Acetic acid (50ml.) was added and the precipitated solid was filtered off, washed withwater and dried. The dry solid was heated under reflux with benzene (21.) for 2 hr. the mixture cooled and filtered to give3a-hydroxy-5apreg'n-16-ene-l1,20-dione (215 g.).

Benzene extracts from several similar experiments were combined andevaporated. The crude solid was redissolved in hot benzene and petroleumwas added until the solution was just clear at ambient temperature, (aninsoluble residue was removed by filtration at this stage). The clearsolution was passed down an alumina column (Woelm alumina activitygrade 1) previously prepared with benzene-petroleum in the ratio 6:4.Elution with the same solvent gave the diene. Elution was terminatedwhen thin layer chromatography indicated the presence of slower runningcomponents in the eluate. The combined fractions were evaporated andtwice crystallised from benzene-petroleum to give5a-pregna-2,l6-diene-l1,20-dione as colourless crystals, m.p. 176177,[a]1;+ 159 (EtOH) -5.." lls9l591;

A max Preparation 8 2B-Ethoxy-3a-hydroxy-5oz-pregn-l6-ene-l1,20-dione.

2a,30z-Epoxy-5a-pregn-16-ene-l1,20-dione (3 g.) was dissolved withwarming in dry ethanol (80 ml.). The solution was stirred and allowed tocool to room temperature. Concentrated sulphuric acid (0.7 ml.) wasadded and the solution was stirred at room temperature for 30 minutes.Potassium bicarbonate solution (10%, 35 ml.) was added and the mixturepoured into ice-cold water (1 litre) and extracted with chloroform (2 X200 ml.). The extract was dried over sodium sulphate and evaporated to acolourless oil (2.73 g.)

' which was purified by preparative TLC in ethyl acetate/petrol l/l theplates being run 3 times and the main UV-absorbing, band separated andrecrystallised from ethyl acetate/petrol to give title compound (950mg.) as fine white crystals, m.p. 89-9l [01],, 77 130.3).

Preparation 9 a. (16/3-1-1)-l'-Pyrazo1ino-(4,3':16a,l7a)-5a-pregn-2-ene-l 1,20-dione 5a-Pregna-2,l6-diene-l 1,20-dione (2.0 g.) in drytetrahydrofuran (40 ml.) was treated with an excess of etherealdiazomethane and the yellow solution was left at room temperatureovernight. The unreacted diazomethane was removed by adding two drops ofglacial acetic acid. The solution was evaporated to a crystallineresidue which was recrystallised from acetone/petrol to give titlecompound (2.07 g.) as white needles.

m.p. 160-16l (with nitrogen evolution). [aln 200(c 1.17). a b.16-Methyl-5a-pregna-2,l6-diene-11,20-dione.

(16B-H)-1'-Pyrazolino-(4',3':1601,17a)-5a-pregn- 2-ene-l 1,20-dione(2.29 g.) was added gradually to dimethylformamide (10 ml.) at 150,nitrogen being evolved. The reaction solution was kept at 150 for 10minutes, and then left to cool. Water (20 ml.) was added and the whitesuspension was extracted with methylene chloride (3 X 25 ml.). Theextracts were combined, washed with water ml.). dried over sodiumsulphate and evaporated to a cream-coloured solid. Recrystallisationfrom petrol containing a little acetone gave title compound (840 mg.) aswhite crystals, m.p. l9l-194, {al 75 A (EtOH) 247 nm (e 9250). c.2a,3a-Epoxy-l6-methyl-5a-pregn-16-ene-1 1,20-

dione 16-Methyl-5a-pregna-2,l6-diene-l1,20 -dione (800 mg.) in methylenechloride (50 ml.) was treated with m-chloroperbenzoic acid 535 mg), andthe solution was left to stand at room temperature overnight. Moremethylene chloride (50 ml.) was added and the solution washed withpotassium bicarbonate solution (5%, m1.) and with water (100 ml.). driedover so dium sulphate and evaporated to a crystalline solid (-1 phuricacid (0.1 ml.). After 10 minutes, potassium bi-' carbonate solution andice-water were added and the fine precipitate (600 mg.) was filtered offand purified by preparative tlc in ethyl acetate, the main band (R,

0.5) being recrystallised from acetone/petrol to give title compound(365 mg.) as white crystals, m.p.

l84-186, [011 51.6 h,,,, (EtOH) 247 nm (69100).

Preparation 10 i 1 la-Hydroxy-l9-norpregna-4,l6-diene-3,20-dione Asolution of a mixture of lla,l7oz-dihydroxy-l9 norpregn-4-ene-3,20-dione(4 g.) and semicarbazide hydrochloride (4 g.) in methanol (200 ml.) wasrefluxed for 2 hr. The methanol was then removed by distillation underreduced pressure and water was added to the residue. The precipitatedsolid was collected by filtration. washed with water and dried over P 05in vacuo. A solution of this solid in a mixture of glacial acetic acid(80 ml.). water (28 ml.) and pyruvic acid (4 ml.) was heated on a steambath for 1 hr. The resulting solution was concentrated under reducedpressure and partitioned between saturated aqueous sodium bicarbonateand ethyl acetate. The organic layer was washed with water, dried (Na S0and evaporated to dryness. The residue was subjected tp preparative tlc(CHCl (CH CO; 15:1) and crystallised from acetone/petroleum ether toafford title compound (1.6 g.) as white needles, m.p. 149.

Preparation 11 19-nor-5 a-pregna-3,l 1,20-trione' via trihydroxyl9-nor-5oz-pregnane A solution of l la-hydroxy-19-norpregna-4,l6-diene-3,20-dione (2.5 g.) in dry tetrahydrofuran (200 ml.) was added over 5mins. to a solution of lithium (5 g.) in liquid ammonia (2.5 litres).The solution was then left for 30 min. Ethanol (ca. 100 ml.) was thenadded until the blue colour had been discharged and the am monia wasthen allowed to evaporate. The residue was partitioned between water andether. The organic layer was washed, dried (Na S and evaporated to givecrude 3g, 1 la,20-trihydroxyl 9-nor-5a-pregnane 1.5 g.). The crudetrihydroxy compound was oxidised in two ways.

a. Acidic potassium dichromate.

A solution of crude 3,l1a-20-trihydroxy-19-nor- Sa-pregnane (4 g.) inacetone (280 ml.) was treated with a solution of potassium dichromate(8.0 g.) in 2N- sulphuric acid (38 ml.) at room temperature for 1 hr. Anadditional quantity of potassium dichromate (8 g.) in 2N'sulphuric acid(38 ml.) was then added and left at room temperature for 15 mins. Thesolution was then partitioned between water and ether and the organiclayer was washed with water, dried (Na S0 and evaporated. The residualoil was subjected to preparative tlc (CHCl and recrystallised fromacetone/petroleum ether to afford title compound (1.04 g.) as whiteprisms, m.p. 151 [01],, 240(c 1.0).

b. Jones Reagent.

A solution of crude 35,11a,20-trihydroxy-l9-nor- Sa-pregnane (1.5 g.) inacetone (40 ml.) was treated dropwise with Jones reagent (5 ml.) [asolution of chromium trioxide (267 g.) in a mixture of concentratedsulphuric acid (230 ml.) and water (400 ml.) made up to 1 litre withwater (8N w.r.t. oxygen)] at room temperature. The resulting solutionwas partitioned between water and ethyl acetate. The organic layer waswashed with water, dried (Na S0 and evaporated. The residue was subjectdto preparative tlc CHCI and recrystallised from acetone/petroleum etherto afford the title compound (0.44 g.).

Preparation 12 3a-Hydroxy-19-nor-5a-pregnane-11,20-dione A solution of19-nor-5a-pregnane-3,l1,20-trione (0.9 g.) in chloroiridic solution (75ml.) [prepared by refluxing a mixture of chloroiridic acid (0.09 g.),90% isopropyl alcohol (200 ml.) and trimethyl phosphite (16 ml.) for 16hr. The solution was neutrallised with triethylamine immediately priorto use] was refluxed for 24 hr. The solution was then cooled,partitioned between water and ether and the organic layer was washedwith water, dried (Na S0 and evaporated. The residue was subjected topreparative tlc (EtoH) was recrystallised from to afford the titlecompound (0.6 g.) or white needles,'m.p. 154", [a],, 200 (c 1.0).

EXAM PLE 78 2B-Ethylthio-3a-hydroxy-5a-pregnane-l 1,20-dione2a.3a-Epoxy-5a-pregnane-l1.20-dione (50 mg.) in dry ether was treatedwith ethanethiol (0.8 mls.) and BF etherate (three drops). The reactionmixture was stirred at room temperature for 20 minutes; then ether (5mls.) and potassium bicarbonate solution (10%, 2.5

ml.) were added. The ether layer was evaporated to about 5 mls.and'purilied by preparative tlc in .ethyl acetate/petroleum ether (2:1)to give a colourlessoil (200 mgs.) which was triturated with acetone andpetroleum ether to give the title compound 174 mg); fine white crystals;m.p. l173; [a],, 93 (c 0.6).

We claim:

1. A Ba-hydroxy steroid of the pregnane or 19- norpregnane seriesselected from the group consisting of a compound of the formula CH2R2wherein:

R is a bromine, fluorine or iodine atom; f' G) alkanoyloxy; (C -Calkanoyloxy substituted with at least one ofa halogen atom or adiethylamino, morpholino or piperidino group; (C -C alkoxy; allyloxy;cyclohexyloxy; phenoxy; benzyloxy; (C C.,-) alkylthio; (C,-C.;) alkoxysubstituted-by at least one of a halogen atom or hydroxy, (C -C alkoxy,(C -C6) alkoxycarbonyl, morpholino, tetrahydrofuranyl, or (C -Calkanoyloxy substituted with at least one of a halogen atom or adiethylamino or morpholino group; alkyl containing up to 9 carbon atoms;hydroxy; nit'rooxy; azido; or tosyloxy;

R is hydrogen or methyl;

R is hydrogen, halogen or (C1-C6) alkanoyloxy;

X is 2 hydrogen atoms or an oxo group; and

Z is 2 hydrogen atoms,

a hydrogen atom and a halogen atom, or a hydrogen atom and a (C,C alkylgroup; and its pharmaceutically acceptable 3a-(C C alkanoyl ester orsuch an ester substituted by at least 1 halogen atom or carboxy ordiethylamino group and its ZO-ethylene ketal, R being hydrogen only whenR is (C,-C alkoxy, X is oxo and Z is 2 hydrogen atoms.

2. A compound according to claim 1 in the form of a 3a-lower -alkanoylester.

3. The compound of claim 1 wherein:

R is hydrogen bromine, or an acetoxy group; and

Z is two hydrogen atoms, a hydrogen atom and a methoxy group, a hydrogenatom and a fluorine or chlorine atom, a hydrogen atom and a methylgroup, or two methyl groups. i

4. The compound of claim 1 wherein:

R is a bromine or iodine atom; acetoxy; p'ropionyloxy; acetoxysubstituted by a chlorine or iodine atom or diethylamino. morpholino orpiperidino; methoxy; ethoxy; i-propoxy; n-butoxy; t-butoxy; allyloxy;cyclohexyloxy benzyloxy; ethylthio; methoxy substituted bytetrahydrofuranyl; ethoxy substituted by a chlorine atom or methoxy.morpholino, cyano or ethoxycarbonyl n-propoxy substituted by a chlorineatom or morpholino; n-butoxy substituted by chloroacetoxy, iodoacetoxy,morpholinoac'etoxy or diethylaminoacetoxy; methyl; n-butyl; or axido; Ris a hydrogen atom or acetoxy; and Z is 2 hydrogen atoms or a methylgroup and a hydrogen atom. 5. The compound of claim 4 wherein R ishydrogen, and X is oxo.

6. The compound of claim 5 wherein Z is two hydrogen atoms.

7. The compound of claim 1 which is ZB-methoxy- 3u-hydroxy-5a pregnane-l1,20-dione.

8. The compound of claim 1 which is ZB-isopropoxy-3a-hydroxy-5a-pregnane-l 1,20 -dione.

9. The compound of claim 1 which is 2/3-(2-chloroethoxy)-3a-hydroxy-Sa-pregnane-l 1,20-dione.

10. The compound of claim 1 which is 2B-acetoxy-3a-hydroxy-5a-pregnane-l 1,20-dione.

' 11. The compound of claim 1 which is2fl-ethoxy-3ahydroxy-l9-nor-5a-pregnane-l1,20-dione.

12. The compound of claim 1 which is 3a-hydroxy- 36ZB-piperidino-acetoxy-Sa-pregnane-l l,20-dione citrate.

13. The compound of claim 1 which is 3oz-hydroxy-2B-propionyloxy-5a-pregnane-l 1,20-dione.

14. The compound of claim 1 which is 2B-n-butyl-3ahydroxy-Sa-pregnane-ll,20-dione.

15. The compound of claim 1 which is ZB-propoxy-3a-hydroxy-5a-pregnane-1 1.20-dione.

l6. 2,8-Ethoxy-3a-hydroxy-Sa-pregnane-l 1.20- dione.

l7. 2B-Methyl-3a-hydroxy-Sa-pregnanc-l 1,20- dione.

l8. ZB-Chloropropoxy-3a-hydroxy-Sa-prcgnane- 11,20-dione.

l9. 2B-Butoxy-3a-hydroxy-Sa-pregnane-l 1,20- dione.

20. 2,8-Bromo-3a-hydroxy-Sa-pregnane-l 1,20- dione.

21. 2,8-lodo-3a-hydroxy-5a-pregnane-l l,20-dionet

1. A 3A-HYDROXY STEROID OF THE PREGNANE OR 19-NORPREGNANE SERIESSELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA
 2. Acompound according to claim 1 in the form of a 3 Alpha -lower -alkanoylester.
 3. The compound of claim 1 wherein: R2 is hydrogen bromine, or anacetoxy group; and Z is two hydrogen atoms, a hydrogen atom and amethoxy group, a hydrogen atom and a fluorine or chlorine atom, ahydrogen atom and a methyl group, or two methyl groups.
 4. The compoundof claim 1 wherein: R is a bromine or iodine atom; acetoxy;propionyloxy; acetoxy substituted by a chlorine or iodine atom ordiethylamino, morpholino or piperidino; methoxy; ethoxy; i-propoxy;n-butoxy; t-butoxy; allyloxy; cyclohexyloxy benzyloxy; ethylthio;methoxy substituted by tetrahydrofuranyl; ethoxy substituted by achlorine atom or methoxy, morpholino, cyano or ethoxycarbonyl n-propoxysubstituted by a chlorine atom or morpholino; n-butoxy substituted bychloroacetoxy, iodoacetoxy, morpholinoacetoxy or diethylaminoacetoxy;methyl; n-butyl; or axido; R2 is a hydrogen atom or acetoxy; and Z is 2hydrogen atoms or a methyl group and a hydrogen atom.
 5. The compound ofclaim 4 wherein R2 is hydrogen, and X is oxo.
 6. The compound of claim 5wherein Z is two hydrogen atoms.
 7. The compound of claim 1 which is 2Beta -methoxy-3 Alpha -hydroxy-5 Alpha -pregnane-11,20-dione.
 8. Thecompound of claim 1 which is 2 Beta -isopropoxy-3 Alpha -hydroxy-5 Alpha-pregnane-11,20-dione.
 9. The compound of claim 1 which is 2 Beta-(2-chloroethoxy)-3 Alpha -hydroxy-5 Alpha -pregnane-11,20-dione. 10.The compound of claim 1 which is 2 Beta -acetoxy-3 Alpha -hydroxy-5Alpha -pregnane-11,20-dione.
 11. The compound of claim 1 which is 2 Beta-ethoxy-3 Alpha -hydroxy-19-nor-5 Alpha -pregnane-11,20-dione.
 12. Thecompound of claim 1 which is 3 Alpha -hydroxy-2 Beta-piperidino-acetoxy-5 Alpha -pregnane-11,20-dione citrate.
 13. Thecompound of claim 1 which is 3 Alpha -hydroxy-2 Beta -propionyloxy-5Alpha -pregnane-11,20-dione.
 14. The compound of claim 1 which is 2 Beta-n-butyl-3 Alpha -hydroxy-5 Alpha -pregnane-11,20-dione.
 15. Thecompound of claim 1 which is 2 Beta -propoxy-3 Alpha -hydroxy-5 Alpha-pregnane-11,20-dione.
 16. 2 Beta -Ethoxy-3 Alpha -hydroxy-5 Alpha-pregnane-11,20-dione.
 17. 2 Beta -Methyl-3 Alpha -hydroxy-5 Alpha-pregnane-11,20-dione.
 18. 2 Beta -Chloropropoxy-3 Alpha -hydroxy-5Alpha -pregnane-11, 20-dione.
 19. 2 Beta -Butoxy-3 Alpha -hydroxy-5Alpha -pregnane-11,20-dione.
 20. 2 Beta -Bromo-3 Alpha -hydroxy-5 Alpha-pregnane-11,20-dione.
 21. 2 Beta -Iodo-3 Alpha -hydroxy-5 Alpha-pregnane-11,20-dione.